Nucleic acid active agents against various plant pathogens

Abstract

The invention relates to newly identified nucleic acids, ribonucleic acids (RNAs) and deoxyribonucleic acids (DNAs), specifically esiRNAs / ERNAs (effective small interfering RNAs) and RNAs derived therefrom, as well as eASO (effective antisense DNA oligonucleotides), collectively referred to as eNAs (effective nucleic acids), which are used in RNA silencing / RNAi or RNA silencing / antisense methods, as active agents against various variable plant pathogens. To identify the eNAs, a screening method, hereinafter also referred to as "eNA screen", was applied for the first time in standardised form to objective (target) RNAs of various plant pathogens. As a result, a new class of these active agents against these pathogens was identified and successfully used against them. The invention further relates to the construction of double-stranded ribonucleic acids, edsRNAs (effectively active double-stranded RNAs), which contain nucleotide sequences of identified esiRNAs / ERNAs or related RNAs derived therefrom, and which can be successfully used in the RNA silencing / RNAi methods as active agents in plant protection against these same variable plant pathogens*.

Description

[0001] Nucleic acid active substances against various plant pathogens Field of the invention The invention relates to newly identified nucleic acids, ribonucleic acids (RNAs) and deoxyribonucleic acids (DNAs), specifically esiRNAs / ERNAs (effectively active small interfering RNAs) and RNAs derived therefrom, as well as eASO (effectively active antisense DNA oligonucleotides), collectively referred to as eNAs (effective nucleic acids), which can be used in RNA silencing / RNAi or RNA silencing / antisense methods as active substances against various variable plant pathogens. To identify the eNAs, a screening method (WO2019001602 A1), hereinafter also referred to as “eNA screen,” was applied for the first time in a standardized form to target RNAs of various plant pathogens. As a result, a new class of these active substances against these pathogens could be identified and successfully used against them. The invention further relates to the construction of double-strandedRibonucleic acids, edsRNAs (effective double-stranded RNAs), which contain nucleotide sequences of identified esiRNAs / eRNAs or related RNAs derived from them, and which can be successfully used as active ingredients in plant protection against these variable plant pathogens* using RNA silencing / RNAi. The term "plant pathogens" here collectively refers to plant-infecting viruses as well as plant-infecting organisms such as nematodes and fungi that have a damaging effect on plants. Background of the invention: RNA interference (RNAi) is a mechanism best characterized in higher eukaryotes but active in the cells of almost all organisms. The RNAi mechanism serves to switch off (RNA silencing) or to modulate gene expression and, as will be explained below, can also be used specifically for these purposes (see, among others, Shabalina and Koonin 2008; Carthew and SontheimerCellular factors, which are described in detail below, inactivate target ribonucleic acid molecules (hereinafter referred to as "target RNAs") via various forms of small ribonucleic acid molecules, which are referred to here by the general term small RNAs, "sRNAs", or modulate the function, such as translation, of these target RNAs. The term sRNAs includes, for example, small interfering RNAs, siRNAs, as well as, for example, micro RNAs, miRNAs, but also other forms of small RNAs that can trigger RNA silencing (see, for example, Borges and Martienssen, 2015; Zhan and Meyers, 2023). The target RNAs originate from pathogens that infect foreign cells or directly from a cell that is part of an organism, even an organism acting as a pathogen, in which RNAi is effective. RNAi is likely an evolutionarily conserved defense mechanism of the cell. RNAi is found in plants, but also in insects,Nematodes, oomycetes, and fungi are a major component of the immune response against pathogens (see, among others, Ding 2010; Zvereva and Pooggin 2012; Gammon and Mello 2015; Guo et al. 2019). The RNAi process will be described below primarily for plant cells and with regard to its function as a defense mechanism, as it is one of the best studied in this area, particularly with regard to its antiviral efficacy (schematically shown in Figure 1). RNAi is also active, with modifications, in a similar form in nematode, oomycete, fungal, and insect cells. RNAi is triggered by ribonucleic acids that contain double-stranded (ds) regions, i.e., two nucleotide strands of different RNA molecules or of the same RNA molecule that are paired (hybridized) via complementary base pairing. RNA molecules whose nucleotide building blocks can form double strands over large areas, possibly hundreds or thousands of nucleotides, are also referred to as “dsRNAs”. TheInduction of RNAi in viral infections: Triggers can be structured, double-stranded regions of viral messenger RNAs (mRNAs) or viral RNA genomes. RNAi is particularly effectively triggered by dsRNA replication intermediates. These are formed during the replication of RNA viruses and consist of complementary RNA double strands that span hundreds or thousands of base pairs. Double-stranded regions of RNAs can be perceived in the cell as so-called pathogen-associated molecular patterns (PAMPs) and thus as "foreign." Detectors include cellular enzymes belonging to the family of type III ribonucleases, known as Dicer or Dicer-like proteins (DCLs) (Fukudome and Fukuhara 2017; Song and Rossi 2017). In the antiviral RNAi immune response of the plant, the proteins DCL2 and DCL4, first characterized in the model plant Arabidopsis thaliana (A. thaliana), play a central role (Deleris et al., 2006; Parent et al., 2015). DCL2 andDCL4 binds dsRNAs and process them by endonucleolytic hydrolysis (cleavage) into siRNAs. siRNAs are short, 21-25 nucleotide (nt) long RNA molecules consisting of two complementary single-stranded RNA components. These so-called "RNA duplexes" are phosphorylated at the 5' end and have a 2-nt single-stranded overhang and 3' hydroxyl groups at the 3' end (Elbashir et al. 2001a; Elbashir et al. 2001b). siRNAs with a length of 21 or 22 nt are particularly effective in antiviral therapy (Deleris et al. 2006). After generation by the DCLs, one strand of the originally predominantly double-stranded siRNAs (see above), the so-called guide strand, becomes active in RNA-induced silencing complexes (RISCs). The main components of the RISCs are so-called Argonaute (AGO) proteins; these resemble RNase H enzymes and can also exhibit endonucleolytic activity. The AGOs bind the guide strand (gs) of the siRNA duplex, while the other strand of the duplex (passenger strand, ps) is removed.and degraded (Meister 2013; Kobayashi and Tomari 2016) (Figure 1). Ten different AGO proteins (AGO1-10) are encoded in A. thaliana; they have different functions, some of which are not yet fully understood. However, it has been conclusively shown that AGO1 and AGO2 are centrally and essentially involved in the plant's antiviral immune response (Carbonell and Carrington 2015). The AGO proteins have different binding priorities for siRNA guide strands. For example, AGO1 binds with high priority to RNAs containing a 5'-terminal U nucleotide, while AGO2 binds with priority to RNAs with a 5'-terminal A nucleotide (Mi et al. 2008; Takeda et al. 2008; Schuck et al. 2013). After binding of the siRNA guide strand by AGO, the corresponding RISC binds to the target RNA. An important role is played by the sequence complementarity of the bound siRNA guide strand with the sequence in the target RNA to which it can hybridize, here astarget site (Liu et al. 2014). Sequence complementarity is naturally highest with the target RNA from which the siRNAs originally originate. Consequently, under natural circumstances, the target RNAs are also those RNA molecules (“cognate RNAs”) that were originally processed into siRNAs. In viral infections, these are viral mRNAs, viral genomes, or viral replication products; in other pathogens, these are usually mRNAs. After association of the AGO / RISC with the regions of the cognate target RNA complementary to the siRNA guide strand, these can be coding or non-coding (untranslated) regions, endonucleolytic hydrolysis (slicing) of the target RNA catalyzed by the AGO protein can occur (Figure 1); This occurs between the nucleotides of the target RNA that are opposite nucleotides 10 and 11 of the siRNA guide strand (Elbashir et al. 2001a; Elbashir et al. 2001c;Alternatively, there is evidence that siRNA-containing AGO / RISCs associated with target RNAs inhibit the translation of these RNAs (Brodersen et al. 2008; Iwakawa and Tomari 2013). The result of the activity of the siRNAs in the RNAi process is therefore always a temporary inhibition of gene expression: The target RNAs are cleaved and degraded, or the synthesis of the proteins encoded by these RNAs is inhibited. The result of RNAi directed against pathogens is thus, via the inhibition of gene expression (RNA silencing), an inhibition of the pathogen's replication (Zvereva and Pooggin 2012). Accordingly, RNAi is already being used specifically to protect plants against pathogens such as viruses (Khalid et al. 2017; Pooggin 2017). DsRNAs, which are derived from the sequences of target RNAs of pathogens, can accordingly be used as antipathogenic agents: They are processed by Dicer enzymes and generate siRNAs, some of which (see below)can be effective in the manner described above. In order to achieve an effect against viruses, the dsRNA must be used in the plant. DsRNA active substances and the resulting siRNAs produced in the RNAi immune system of plants, nematodes, fungi, oomycetes and insects, which act against the pathogens' own RNAs (usually mRNAs), can be used as herbicides, nematicides, fungicides or insecticides in and on the plant. As an alternative to dsRNAs, however, sRNAs such as siRNAs, miRNAs or other forms of small RNAs active in the RNAi process (e.g. piRNAs, tasiRNAs, vasiRNAs etc.) can also be used directly as antipathogenic agents (see, among others, Tomilov et al. 2008; Banerjee et al. 2017; Majumdar et al. 2017; Price and Gatehouse 2008). As will be explained in more detail below, all of these sRNAs act according to the same principle as siRNAs: Basically, a single-stranded component of these sRNAs is incorporated into RISC in an analogous form andin the RNA silencing / RNAi process against a target RNA by slicing or by inhibiting translation. As already explained, RNAi is practiced for the artificial "knockdown" of gene expression by introducing siRNAs or other related or derived sRNAs, such as miRNAs, into cells as active substances in order to specifically influence the function of target RNAs. In this way, as described, cellular gene expression, but also the gene expression of pathogens, can be suppressed or modulated at the mRNA level. Furthermore, the replication of viruses, whose genomes are RNA molecules, can be prevented by silencing these genomes. For the purpose of artificially inducing RNAi, an organism can produce (express) RNA active substances itself. This is already practiced in plants. In this case, we speak of “host-induced gene silencing” (HIGS): plants express dsRNAs, siRNAs or other sRNAs such as miRNAs in the forma transgene (Herrera-Estrella et al. 2005; Dong and Ronald 2019; Koch and Wassenegger 2021) to achieve protection against pathogens such as viruses, but also nematodes, fungi, insects, oomycetes, or other parasitic plants. This can be achieved permanently (and only permanently does this process make sense) by stably integrating the respective nucleic acid-expressing foreign gene into the genome of the organism to be protected. Obtaining transgenes is complex, not possible with all plants, and unsuitable for many applications. The latter applies particularly to applications against rapidly changing pathogens: A transgenic crop obtained after years of development may still be infected by variants of these pathogens (Jan et al. 2000; Savenkov and Valkonen 2001; Simón-Mateo and García 2006; Tabashnik et al. 2013; Kung et al. 2015). Furthermore, the use of transgenic plants (genetically modified organisms (GMOs)) in agriculture andHorticulture is prohibited in many countries (Lucht 2015). Alternatively, RNA drugs can be used in so-called topical / transient applications. In this case, dissolved RNA, e.g., in the simplest case, in the form of a spray, is applied to a target organ or target cells of an organism. There, the RNA is partially taken up via mechanisms that are still incompletely understood. Improving the uptake mechanisms of the negatively charged RNA molecules in target cells, which are inefficient, is the subject of intensive research. So-called "spray-induced silencing" (SIGS), in which RNA is applied in the form of a solution (e.g., as irrigation water or spray) on and in plants, is ecologically much less critical than HIGS, also due to the biodegradability of RNAs, and is therefore attractive for the administration of RNA drugs (Dalakouras et al. 2020). In addition, processes have been developed in the last five years or so that the production of RNA on a gram-per-gram basis.or even kilogram scale (Robinson et al. 2014; Kaur et al. 2018). For example, the price of one gram of dsRNA, which is needed for treatment in a small field of crops, has been reduced from over US$100,000 to less than US$2 (Le Page 2017). As already mentioned above, in the case of plant protection, the goal of topical / transient applications of RNAs is either that plants internalize the RNA active substances, e.g., to inhibit viral replication, or that attacking pathogens such as fungi, nematodes, insects, or parasitic plants take up RNA active substances via the surface of the plant to be protected, which then become active in the RNAi system of the respective organisms against essential target RNAs of the pathogens (see also above: Tomilov et al. 2008; Banerjee et al. 2017; Majumdar et al. 2017; Price and Gatehouse 2008). However, the use of RNA active substances in topical / transient applications is limited for various reasons.not yet fully developed. One reason is the aforementioned inefficient uptake of RNA into target cells. Therefore, intensive work is being carried out on methods to stabilize RNA drugs through chemical modifications of the nucleotide building blocks and / or to deliver them to the site of action in the cytoplasm of the target cells through physical or biochemical processes (Dowdy 2017; Setten et al. 2019; Dalakouras et al. 2020). However, there are significant differences from application to application and from organism to organism. Another reason concerns the fact that both natural and artificially induced RNA silencing / RNAi processes are generally inefficient. This is particularly due to the fact, now well-established by numerous data, that although Dicer / DCl activities generate an enormous number (a "pool") of siRNAs from target RNAs, only a few siRNAs from such a pool are ultimately effective on the target RNA (Figure 1). The reason for this isIn particular, target RNAs are generally highly structured, with only a few attack sites (here referred to as accessible sites, "a-sites") being accessible for effective association of sRNA / AGO / RISC with the complementary target sites and thus for silencing. This is especially true for target RNAs from pathogens: The structure of pathogen target RNAs is often adapted (attenuated) through co-evolution with the target organism to the extent that they best evade RNA silencing / RNAi. a-sites are defined here as regions of a target RNA that are accessible to nucleic acid agents. An a-site can correspond to a "target site." A target site is defined here as the sequence of a target RNA to which a single-stranded nucleic acid such as an siRNA guide strand or an antisense oligonucleotide (see below) can hybridize via complementary base pairing. An a-site can also contain larger regions of a target RNAinclude, for example, RNA structural motifs that are particularly easily accessible and contain one or more target sites of single-stranded nucleic acids. In SIGS, double-stranded versions of target RNAs, for example, dsRNA versions of mRNAs or viral genomes, have so far been used for RNAi (Robinson et al. 2014). It is important to note here that ALL dsRNAs used for RNAi to date have comprised either the complete sequence or a longer, uninterrupted section (usually several hundred nucleotides) of the corresponding target RNA on one strand (see also the control RNA dsCMV used in Figures 9, 10, 11 and 15). The second RNA strand was a second molecule with a completely complementary sequence. Alternatively, so-called hairpins have also been used. The two complementary RNA strands are located in the same molecule and are separated by a so-called “spacer”, a largely unstructured, single-stranded sequence of anyNucleotide composition and length are separated. They thus form an incomplete double strand, a so-called hairpin. After entering the plant cell, dsRNAs or dsRNA hairpins are processed by the DCLs into an siRNA pool, analogous to normal target RNAs. However, this pool is subject to the problem mentioned above: only very few of the siRNAs generated from these "conventional dsRNAs" are effective (see also the schematic representation in Figure 1 as well as Figures 10 and 15). "Conventional dsRNAs" means that one strand of these RNAs consists of an exact copy of the targeted target RNAs and that this strand is then hybridized with a complementary RNA strand. As explained, dsRNAs constructed according to this principle are currently used in RNAi-mediated plant protection. The remaining siRNAs in the pool, ie the overwhelming majority, can non-specifically saturate cellular AGO / RISC (they thus act as a “decoy” forthe AGO / RISC), which can even lead to RNA silencing / RNAi being inhibited by the use of conventional dsRNAs or dsRNA hairpins. Furthermore, there is a risk that siRNAs from a pool may trigger silencing on non-targeted RNAs ("off-target effects"), e.g., via incompletely complementary base pairing of guide strands with these other RNAs, which is nevertheless sufficient to form functional RISC (Jackson and Linsley 2004; Jackson et al. 2006; Senthil-Kumar and Mysore 2011; Casacuberta et al. 2015; Kamola et al. 2015). In summary, the use of dsRNAs, which generate a particularly large number of uncharacterized siRNAs that are not active on the target RNA, is problematic (Qu et al., 2012; Dalakouras et al., 2016). The same applies to dsRNAs from which other forms of sRNAs are generated. Until recently, the few siRNAs that are effective in RNAi, here "esiRNAs" or "ERNAs" and in the following combined"esiRNAs / eRNAs" cannot be reliably identified and deployed from siRNA pools. Many siRNA or sRNA drugs were designed to either target regions of a target mRNA that encode conserved motifs of a protein, or they were identified based on unreliable in silico predictions of α-sites in the target RNAs and then tested for their efficacy in very complex empirical studies ("trial and error") (Birmingham et al. 2007; Cerritelli and Crouch 2009; Miozzi et al. 2013; Fakhr et al. 2016; Carbonell et al. 2018; Eastman et al. 2018; Han et al. 2018; Qureshi et al. 2018; Setten et al. 2019). Only in recent years, mainly through work from our laboratory, has it been possible to establish an experimental screening method, the so-called “eNA-screen”, with which it is possible to reliably detect a-sites in a wide variety of target RNAs in a short time frame (Schuck et al. 2013;Gago-Zachert et al. 2019; WO2019001602 A1; WO 2022 / 200407; schematically shown in Figure 1). Knowledge of the a-sites can be used to identify esiRNAs / eRNAs that are reliably and efficiently effective in the RNA silencing / RNAi process against the respective target RNAs. The terms reliable and efficient are precisely defined: The "eNA screen" is a multi-step in vitro procedure (see further description below) in which the efficiency of hydrolysis of the target RNA by an identified siRNA is ultimately measured in a so-called slicer (cleavage) assay. Efficient siRNAs – and thus referred to as esiRNAs / ERNAs – are those that hydrolyze at least 25% of the target RNA used in a standardized and stringent slicer assay (see also Tables 1, 2, 7, and 8). As demonstrated, these esiRNAs / ERNAs reliably demonstrate a high degree of antipathogenic efficacy inThe respective in vivo system, which in the majority of cases correlates with the aforementioned ability to hydrolyze the target RNA in the slicer assay (Gago-Zachert et al., 2019; see, for example, Figures 2-6). The ability to use esiRNAs / ERNAs exclusively against target RNAs and thus against pathogens significantly increases the efficiency of RNA silencing / RNAi processes. Furthermore, the use of esiRNAs / ERNAs increases the specificity of RNAi: The likelihood of off-target effects on non-targeted RNA molecules and thus unfavorable and undesirable side effects of RNA drugs is significantly reduced. As already explained, esiRNAs / ERNAs can be defined by identifying a-sites in target RNAs. In other words, in the a-sites, sequences, target sites, are accessible, through which esiRNA / ERNA guide strands can bind to the target RNA (hybridize via complementary base pairing), and through the activity of the RISC, theTarget RNA is then inactivated in the manner described (i.e., via endonucleolytic cleavage or translation inhibition (see above)). An analogous effect can also be achieved by related sRNAs, such as miRNAs, whose sequences can be deduced from the sequences of esiRNAs / ERNAs and which can then be used in an analogous RNA silencing / RNAi process to esiRNAs / ERNAs. Only recently, it was demonstrated that the identification of a-sites in target RNAs and the definition of esiRNAs / ERNAs whose guide strands can bind to target sites in these a-sites simultaneously allows the definition of antisense deoxyribonucleic acid (DNA) oligonucleotides (ASOs) that can also bind to these target sites (WO 2022 / 200407). In analogous terminology, ASOs derived from esiRNAs / ERNAs are referred to as eASOs. eASOs have DNA sequences homologous to single strands of esiRNAs / ERNAs (i.e., deoxynucleotides instead of ribonucleotides; thymidine instead of uridine) andcan also hybridize to the respective target sites in the a-sites of the target RNAs and also cause RNA silencing. ASOs, like sRNAs, can be used transiently; in so-called "antisense processes," they act via mechanisms different from those of sRNAs. In this context, two of these mechanisms are important: First, the formation of a DNA:RNA heteroduplex between the single-stranded ASO and the target RNA can inhibit the translation process of the RNA in the cytoplasm. On the other hand, the formation of DNA:RNA heteroduplexes can activate RNase H endonucleases (in eukaryotic cells, RNAase H1 and / or RNAase H2) in the nucleus or cytoplasm, which then, similar to AGO / RISC, catalyze the degradation of this target RNA guided by the binding of the single-stranded ASO to the complementary RNA (Shen and Corey 2018; Bennett 2019; WO 2022 / 200407; Wdowikowska and Janicka, 2021, Crooke et al., 2021). Optimally active ASOs have a length of 12-20nucleotides (Crooke et al., 2021). Accordingly, eASOs can be easily derived from 21, 22, 23, or 24 nt long esiRNAs / ERNAs. The following text is essentially limited to the description of the activity of esiRNAs / ERNAs. Analogous findings also apply to other related sRNAs, such as miRNAs and eASOs, whose RNA or DNA sequences can be derived from the sequences of identified esiRNAs / ERNAs: Due to the identical sequence, the single strands of such sRNAs or the eASOs can bind to the same target sites in the corresponding target RNAs and thus can also be used in RNA silencing / RNAi or RNA silencing / antisense methods for pathogen control (WO 2022 / 200407). Collectively, esiRNAs / ERNAs identified via the "eNA screen" and the related sRNAs and eASOs derived from them are referred to as eNAs (effective nucleic acids). It should also be noted that RNA and DNA active substances incan be used in a chemically modified form: Chemical modifications, conjugates, or the construction, including so-called "gapmers" or "mixmers," can significantly improve the potential of siRNA- or ASO-based agents in RNAi or antisense methods in vivo (Setten et al., 2019; Wdowikowska and Janicka, 2022; Crooke et al., 2021; see also claims). Knowledge of a large number of a-sites (and thus target sites) of a target RNA is particularly important for methods aimed at combating variable pathogens. In particular, viruses with an RNA genome and an RNA-dependent RNA polymerase (RdRp) as the main enzyme of viral replication exhibit high plasticity (variability) and thus the potential for rapid development of resistance to antiviral agents. Viral RdRps have no or only an inefficient editing function, which causes errors in the incorporation of nucleotides into newly synthesized daughter nucleic acid strandscan correct. The mutation and evolution rate of RNA viruses during replication is correspondingly high: this is referred to as "antigenic drift." The mutation and evolution rate of viruses whose genome is divided into several segments is particularly high. When a cell is co-infected by different viruses, these segments can sort into completely new combinations – this is referred to as "reassortment." This leads to "antigenic shifts," significant genetic changes that can lead to the generation of viruses with completely new properties and pose a great danger to the respective host because there may not be an effective immune response against these viruses ("viral escape"). However, high variability can also be found in other organisms, especially those that are under strong selective pressure. This is the case with plant pathogens that are routinely treated with antipathogenic substances. These mutate "underthese substances" and develop resistant forms. This applies, for example, to nematodes and fungi that are conventionally treated with nematicides or fungicides in agriculture and horticulture. However, by applying a broad spectrum of eNAs identified or derived via the "eNA screen" in HIGS or SIGS, the possibility of developing pathogen forms that become resistant to an antipathogenic treatment (escape) in the various organisms should be drastically limited. Broad spectrum means that two or more eNAs are used against one target RNA or that two or more eNAs are used that are directed against different target RNAs of the target organism. Using the same approaches, a broad-spectrum effect could also be achieved against pathogen variants (which may arise, for example, during a viral epidemic). Finally, by using different eNAs against different target RNAsBroad-spectrum protection against various pathogens can be achieved. The use of effectively active eNAs offers the following application advantages: (i) The ability to combine different esiRNAs / ERNAs allows the specificity and efficiency of RNA silencing / RNAi methods to be maximized (schematically shown in Figure 1). The same applies to other sRNAs whose sequence is derived from esiRNAs / ERNAs. The same applies to eASOs whose sequence is derived from esiRNAs / ERNAs and which are used in antisense methods. (ii) An RNAi immune response can be quickly and specifically adapted to pathogens that are subject to significant changes due to antigenic drifts or antigenic shifts or that can arise in a completely new form by recombination of anti-pathogenic esiRNAs / ERNAs. The same applies to other sRNAs derived from esiRNAs / ERNA. The same applies to esiRNA / ERNA derived eASOs, which areAntisense methods should be used. (iii) The economic production of nucleic acid-based active substances should significantly increase the acceptance of the use of RNAi or antisense methods, e.g., in plant production. SIGS approaches can be carried out more efficiently, and the use of transgenic approaches can be significantly reduced. (iv) To optimally enable the simultaneous use of esiRNAs / ERNAs and simultaneously improve the usability of RNA in HIGS and SIGS methods, these should preferably be used in the form of dsRNAs. Such so-called "edsRNAs" should contain the nucleotide sequences of several esiRNAs / ERNAs (or other sRNAs derived from them) identified by "eNA screens" (schematically shown in Figure 1). As a general advantage, dsRNAs have a significantly reduced degradation rate (increasedHalf-life) in HIGS and SIGS methods (Bachman et al. 2020) and therefore significant application advantages. Problem / Task In plant protection, the control of highly variable pathogens involves the task of inactivating the target RNAs of these pathogens with adaptable, effective nucleic acid agents, thus preventing their replication. The objective technical task of the invention is therefore to protect plants against various, variable pathogens using sustainable nucleic acid-based methods. To solve this task, the invention, through the application of the "eNA screen," provides various nucleic acid-based agents (eNAs) that are efficiently effective in RNAi or antisense processes against three important plant pathogens, as well as methods for their production and methods for their application. As explained above, the term "efficient" is specifically defined as a common technical feature of the eNAs used. In one aspect, the invention relates toRNAi methods employing one or more esiRNAs / ERNAs or related sRNAs, or antisense methods employing one or more eASOs whose sequences were derived from esiRNAs / ERNAs. Active esiRNAs / ERNAs or other sRNAs or eASOs derived from them (collectively referred to as eNAs) are intended to have reliably high, effective antipathogenic efficacy and, when used in combination, be directed against different target RNAs or different regions (target sites) of target RNAs in order to reliably combat even highly variable pathogens. In a further aspect, the invention relates to RNAi methods using edsRNAs, a completely new form of dsRNAs according to the invention, which contain the nucleotide sequences of esiRNAs / ERNAs or sRNAs derived therefrom and which are processed into these esiRNAs / ERNAs or sRNAs during the RNA silencing / RNAi process. The nucleic acid-based active substances of the invention can be used againstRepresentatives of various classes of variable or highly variable pathogens that infect the host organism plant are generated or applied. As stated, the most important variable plant pathogens include viruses, nematodes, and fungi. The invention is particularly advantageous because the nucleic acid-based active ingredients according to the invention can be generated or applied against economically particularly important representatives of these pathogens. One representative of an economically important, highly variable viral pathogen in plants is Cucumber mosaic virus (CMV). One representative of an economically important, variable nematode pathogen in plants is Meloidogyne incognita (M. incognita). One representative of an economically important, variable fungal pathogen in plants is Botrytis cinerea (B. cinerea). By solving the problem of the invention, a broad range of effective eNAs is provided that can be used as active ingredients in plant protection, individually or in combination, against theseimportant pathogens. "eNA-screen" method used The published or patent-pending method described here as "eNA-screen" (WO 2019 / 001602) was used to identify eNAs. It was applied for the first time in a new, standardized and stringent form to the target RNAs of Cucumber Mosaic virus, Meloidogyne incognita and Botrytis cinerea named below and led to the first-time identification of a class of eNAs effective against these pathogens in RNA silencing, i.e. esiRNAs / ERNAs and their derived sRNAs, eASOs and edsRNAs (see the following description). The eNA-screen method consists of three steps. (i) A target RNA, which can be a genomic RNA, an mRNA, or a dsRNA, is exposed to a cytoplasmic extract from plant cells (Nicotiana tabacum BY-2 cells), the so-called “BYL” (where L stands for “lysate”). The (endogenous) DCLs present in the extract generatean siRNA pool containing, among other things, 21, 22, 23, and 24 nt siRNAs as main products. The siRNA pool is analyzed in its entirety by next-generation RNA sequencing (NGS, RNA-Seq). (ii) RISCs are reconstituted in the extracts with the siRNA pool generated in (i) and with an AGO protein of choice. For this purpose, the AGO protein is translated in vitro in the extract from an added mRNA. The resulting AGO / RISCs are immunoprecipitated, and the siRNA strands enriched by binding to AGOs are identified by RNA-Seq. The RNA-Seq data from step (i) are used for comparison to define enrichment in the respective AGO / RISC. (iii) From the siRNAs collected in (ii), those previously identified in the respective AGO / RISC are finally analyzed using further in vitro assays in which the respective AGO / RISCs are tested for endonucleotic cleavage (slicing) (referred to below and in the figures as “slicer assay”).Enriched siRNAs are identified that induce efficient slicing of the target RNA. As already explained, such siRNAs are defined as esiRNAs / ERNAs if they induce the hydrolysis of 25% or more of the quantity of target RNA used in the respective assay in a standardized and stringently conducted in vitro slicer assay with the appropriate AGO / RISC. Further validation steps then test the efficacy of the respective esiRNAs / ERNAs in vivo. Different methods adapted to the respective target pathogens are used here. From the esiRNAs / ERNAs identified in this way, other sRNAs and eASOs are derived based on the nucleotide sequence sequence. These can also be tested in slicer assays in BYL. In eASO, the active components are RNAase H enzymes (see, for example, WO 2022 / 200407). Target organisms The plant pathogenic Cucumber mosaic virus (CMV) CMV, the type-determining virusof the genus Cucumovirus (family Bromoviridae), is a plant pathogen of great economic importance (Scholthof et al., 2011; Rybicki, 2015; Gallitelli, 2000). CMV has a tripartite-segmented, single-stranded (ss) positive (+)-strand RNA genome. The three genomic RNAs 1 (3.3 kb), 2 (3.0 kb), and 3 (2.2 kb), which are packaged in three different virus capsids and only trigger an infection together, have a cap at the 5' end and a tRNA-like structure at the 3' end. Due to the segmentation of the genome, CMV is a reassortant virus with the associated high mutation rate: i.e., in addition to antigenic drift, caused by the viral RdRp, the virus displays antigenic shifts. After entering the host cell, the three genomic RNAs act as mRNAs due to their (+) orientation ((+) means sense orientation like an mRNA). RNA 1 and RNA 2 code for the proteins “1a” (111 kDa) and “2a” (97 kDa), respectively. The 2a protein is the RdRp; together with 1aIt forms the viral component of replicase, which catalyzes genome replication and the transcription of subgenomic (sg) RNAs. During the RNA replication process (not described in detail here), the replicase transcribes complementary (-)RNA copies of the viral RNAs. These then serve both as templates for the synthesis of new (+)RNA molecules and as templates for the synthesis of subgenomic sgRNAs. One sgRNA, sgRNA 4 (1.1 kb), is transcribed from the (-)RNA copy of RNA 3 produced during replication and is packaged together with it into a capsid. RNA 3 itself encodes the 30 kDa "movement protein 3a"; sgRNA 4 encodes the 24 kDa "capsid protein CP." 3a and CP are essential for both cell-to-cell and systemic movement of the virus throughout the plant during the infection process. Another subgenomic RNA, sgRNA 4A (0.7 kb), is transcribed from the (-)RNA copy of RNA 2. This encodesa viral suppressor of RNA silencing (VSR), "2b" (15 kDa). 2b interferes with the RNA silencing / RNAi process, among other things by sequestering (high-affinity binding) the siRNAs generated during the process. All five gene products influence the spread of the virus in the plant and thus also its virulence in a host-specific manner. During infections, additional satellite RNAs can be produced during viral RNA replication, the presence of which can significantly influence pathogenesis (Gallitelli, 2000; Garcia-Arenal et al., 2008; Jaquemond, 2012; Roossinck et al., 2001; Roossinck et al., 2002; Palukaitis, 2016; Nouri et al., 2014; Mochizuki and Ohki 2012). CMV strains are roughly divided into two subgroups, 1(I) and 2(II), with the strains of subgroup I being further divided into two subgroups (A and B) (see also below and Figure 7). While within a subgroup the sequence similarities are high (subgroup I: > 88%; subgroup II: > 96%), they arebetween the subgroups only 70-75%. CMV strains of subgroups IA and II are distributed worldwide; those of subgroup IB occur mainly in East Asia (Garcia-Arenal et al., 2008; Jaquemond, 2012; Nouri et al., 2014; Mochizuki and Ohki 2012). The serological differentiation index (SDI) between the CMV subgroups is approximately 1-2. These differ from the other cucumoviruses PSV (Peanut stunt virus) and TAV (Tomato aspermy virus), each with an SDI of 6-7. Like other segmented RNA viruses, CMV has a high degree of variability. This is due to the accumulation of mutations through antigenic drift and shift processes (Scholthof et al., 2011; Rybicki, 2015; Gallitelli, 2000). In contrast to other members of the Bromoviridae family, CMV strains have a very broad collective host range and infect more than 1200 plant species in over 100 families of monocotyledons and eucotyledons. These include important fruit, vegetable, and ornamental plants such asFabaceae, Cucurbitaceae, Convolvulaceae, and Solanaceae. CMV is thus the plant virus with the broadest host range, affecting important crops such as beans, beets, carrots, celery, lettuce, peppers, melons, squash, tomatoes, and spinach (Scholthof et al., 2011; Garcia-Arenal et al., 2008; Jaquemond, 2012; Mochizuki and Ohki 2012). CMV infections cause, among other things, severe systemic mosaic symptoms, leaf deformation, systemic necrosis, chlorosis, dwarfism, and fruit lesions (Garcia-Arenal et al., 2008; Jaquemond, 2012; Holeva et al., 2021). CMV can interact synergistically with potyviruses, tobamoviruses, and Potato virus X (PVX) in nightshade plants, as well as with potyviruses in cucurbit hosts (Scholthof et al., 2011; Gallitelli, 2000; Jaquemond, 2012). CMV particles are transmitted by more than 80 aphid species in 33 genera in a non-persistent, stylet-borne manner. Furthermore, depending on the plant species, transmission by infectedSeeds are sown (Jaquemond, 2012; Ali and Kobayashi, 2010; O'Keefe et al., 2007). Furthermore, there are indications that the virus can survive the winter months in seeds, which then become a significant source of primary infections at the beginning of the growing season. Due to its wide range of host plants, its worldwide distribution, and its non-persistent transmissibility by numerous aphids, CMV is considered one of the plant viruses of greatest economic importance and one of the most important viruses in annual crops worldwide (Scholthof et al., 2011; Rybicki, 2015). Crop losses vary from year to year at different locations and are difficult to quantify, especially in cases of mixed infections. Estimates from the 1990s and 2000s provide insight, for example, in China, which assume a tomato harvest of 25%-50%, or in Spain, a melon harvest of 60% or a pepper harvest of 80%. In the case of the occurrence of a necrogenic satellite RNA with certainCMV strains have been recorded in Spain and Italy, causing losses of 80%–100% of tomato plants in 70% of cultivation areas (Gallitelli, 2000). Remarkably, new CMV hosts and new CMV-induced plant diseases are being described each year. Increased aphid activity in northern temperate regions due to climate change is expected to lead to further epidemics (Scholthof et al., 2011; Nicaise, 2014). However, CMV is also becoming increasingly important in tropical and subtropical regions, particularly where mixed crops are cultivated. Control measures based solely on the use of pesticides against aphids are not very effective (Gallitelli, 2000). However, approaches using transgenic plants or RNA-based approaches for plant protection have also been unsuccessful, largely due to the high variability of the virus (Nicaise, 2014). Summary of the invention To solve the problem,Within the scope of the invention, the eRNA screen method is used to characterize esiRNAs / ERNAs against various genomic CMV RNAs that reliably exhibit high antiviral efficacy. In addition to a generally high antiviral efficacy against the cognate target RNAs, these esiRNAs / ERNAs or variants of these esiRNAs / ERNAs should also be antivirally effective against various CMV variants. Furthermore, dsRNAs, so-called "edsRNAs," preferred for HIGS and / or SIGS procedures were generated. From these dsRNAs, significant quantities of esiRNAs / ERNAs are produced during the RNA silencing / RNAi process and, accordingly, also exhibit reliable and efficient antiviral activity. From the esiRNAs / ERNAs characterized in this way, other sRNAs or eASOs could also be derived, which can also be used in RNA silencing / RNAi procedures or in RNA silencing / antisense procedures against CMV. The plant pathogenic nematode Meloidogyne incognita Nematodes (roundworms) are evolutionarily theoldest multicellular worms. In the numerous, moist habitats in which they occur, they often represent the largest group in the metazoan fauna, both in terms of the number of individuals and species diversity (Wikipedia). They are very simply structured: their bodies are limbless, cylindrical, elongated, smooth, and surrounded by an elastic cuticle. The cuticle is secreted by a layer of epidermal cells and forms the exoskeleton of the nematode (Bird and Bird, 1991a). The cuticle is permeable to ions and water and regulates the hydrostatic pressure of the nematode body. Most nematodes undergo four molts during their development, from the juvenile stage (stages J1 to J4) to reaching the adult stage. During this time, the cuticle is either completely shed or, as in the case of Meloidogyne, partially absorbed (Perry and Moens, 2011). Beneath the epidermis, muscles are arranged longitudinally along the inner side of theThe worm's body is oriented around a network of nerves, which are activated by two nerves on the dorsal and ventral sides, which also run longitudinally and are connected by nerve rings (Bird and Bird, 1991b). The worm's head has some sensory organs and a "mouth" that opens into a muscular pharynx (throat). The latter serves as a pump to draw food into the adjoining intestine. The intestine opens into a long, simple intestinal cavity without muscles and finally into an anus near the tip of the body. There is no vascular system for the distribution of digested food and no respiratory system for the intake or distribution of oxygen. Instead, nutrients and waste are distributed within the pseudo-celomic body cavity, the contents of which are regulated by an excretory duct along each side of the body (Bird and Bird, 1991c). One nematode subgroup is plant-parasitic nematodes (PPN). PPN infect many plant species and cause enormous crop losses worldwide (Blok et al., 2008).Despite very different lifestyles and feeding strategies, all PPNs possess a hollow, protruding spine designed to pierce the wall of plant cells and inject secretions and / or enzymatically active proteins that facilitate infection and nutrient uptake. These secretions and proteins are produced by three esophageal "salivary glands," the cuticle, and chemosensory organs (Perry, 1996; Semblat et al., 2001; Curtis, 2007). Among PPNs, the so-called "sedentary endoparasites" cause the greatest economic damage. These include root-knot nematodes (RKNs), of which Meloidogyne species, including Meloidogyne incognita, are the most significant plant pathogens (Trudgill and Blok, 2001), causing estimated crop losses of approximately €10 billion per year worldwide. RKN are found particularly in temperate and tropical regions of the world (Blok et al., 2008; Abad and Williamson, 2010). They infectthousands of plant species, including virtually all cultivated plants, and they cause typical root deformations (galls), which lead to weak and low-yielding plants. The life cycle of RKNs extends from 3-10 weeks, depending on the nematode species and environmental conditions. The worm-like juveniles of the second stage (J2) hatch from the eggs into the soil to infect the host's roots. In the pre-parasitic phase, the J2 usually penetrate the root tissue behind the root tips by physically piercing the root cells with their stylet. At the same time, they release cell wall-altering enzymes that enable further migration into the root tissue and between the cells to the root tip. From there, they migrate into the vascular cylinder of the plant (Perry and Moens, 2011) and induce the formation of specialized feeding sites in the form of so-called giant cells (GCs). GCs are hypertrophied and multinucleated. They arise through repeated nuclear divisions andCell growth in the absence of cell division (Jones and Payne, 1978; Caillaud et al., 2008) and are the nematode's sole source of nutrients. This sac pierces the cells to gain access to the cytoplasm, while secretions alter the hydrostatic pressure of the cells, allowing easy nutrient uptake (Abad and Williamson, 2010). Divisions of the vascular cells and phagocytes surrounding the nematode lead to the formation of a typical gall. After establishing feeding sites, the J2s become sedentary and then develop into adult females or males through three further molts (parasitic J3 and J4). The females are sedentary, while the males become mobile again and migrate from the root into the soil. Mitotic parthenogenesis is the reproductive mode of the RKN (Castagnone-Sereno et al., 2013); Sex is determined by environmental conditions; under poor nutritional conditions, the number of males increases(Papadopoulou and Triantaphyllou, 1982). At the end of their development, the female RKN become pear-shaped. They produce hundreds to thousands of eggs in a protective, gelatinous matrix on the outer surface of the root, which are released directly into the rhizosphere. Within the egg, the first-stage juveniles molt after embryogenesis into J2, which then hatch to continue the life cycle under favorable conditions in a suitable host (Hussey and Mims, 1991; Chitwood and Perry, 2009; Curtis et al., 2009). For a long time, various chemicals such as methyl bromides and carbamates were used as nematicides. However, most are now banned due to the potential environmental and health risks associated with their use. An alternative method for PPN control is crop rotation, in which nematode-resistant crops are planted successively in different seasons. However, this practice has limitations:Some nematodes, such as Meloidogyne, have such a broad host range that it is difficult to select suitable crops to interrupt the infestation cycle. Biological control of PPN involves the use of one or more organisms, such as nematophagous fungi or bacteria. These are introduced into the soil, where they attack the nematodes without affecting plant growth (Evans et al., 1993). However, such "nematode predators" are difficult to manage on a large scale. Furthermore, environmental factors such as soil texture, moisture, temperature, and pH significantly influence the survival of biocontrol agents (Chen and Dickson, 2004; Stirling, 2014), which does not facilitate their use. For nematodes such as Caenorhabditis elegans (C. elegans), but also Meloidogyne incognita (M. incognita), it has been described that they take up siRNAs and also dsRNAs via the nutrient uptake mechanism described above, and that siRNAs are then also present in the body of theAnimals can become active in the worm's RNA silencing / RNAi system through uptake into cells, e.g. in a nematicidal manner by inactivating mRNAs of essential proteins (Arguel et al., 2012; Bakhetia et al., 2005; Banakar et al., 2020; Chaudhary et al., 2019; Dalzell et al., 2010a; Dalzell et al., 2010b;Danchin et al., 2014;Dong et al., 2015;Iqbal et al., 2012; Summary of the invention: Analogously to the method described above for CMV, esiRNAs / ERNAs and edsRNAs were characterized that reliably exhibit high nematicidal activity against various variants of M. incognita. From the esiRNAs / ERNAs characterized in this way, other sRNAs or eASOs could also be derived, which can also be used in RNA silencing / RNAi methods or in RNA silencing / antisense methods against M. incognita. The plant pathogenic fungus Botrytis cinerea Botrytis cinerea(Teleomorph: Botryotinia fuckeliana), the main causative agent of gray mold disease, is an aggressive necrotrophic fungal pathogen that can infect a large number of plant species (more than 200 species) (Elad, 1997; van Kan, 2006; Choquer et al., 2007; Williamson et al., 2007; Nakajima & Akutsu, 2014). B. cinera secretes nonspecific phytotoxins that kill cells of a broad spectrum of plants (Pinedo et al., 2008). The economic damage caused, amounting to 10–100 billion US dollars per year worldwide, with up to 40% losses in greenhouse and field crops when chemical control agents are not used, makes B. cinerea one of the 10 most important plant fungal pathogens (Dean et al., 2012; Pedras et al., 2011; Villa Rojas et al., 2012). The use of chemical fungicides leads to significant environmental pollution (Malhat et al., 2015; Oliveira et al., 2015; Tomenson and Matthews, 2009) and is offset by its nutritional versatility.of B. cinerea. Furthermore, several cases of fungicide resistance in B. cinerea have been reported (Leroux, 2007). Taxonomically, B. cinerea belongs to the phylum Ascomycota in the class Leotiomycetes and the family Sclerotiniaceae (Garfinkel, 2021). Two groups, I and II, have been proposed as phylogenetic species. The strains of group I (also called "Botrytis pseudocinerea") and group II ("B. cinerea sensu stricto") differ in their ecology and fungicide resistance patterns (Fournier et al., 2003, 2005). The genomes of two strains (B05.10 and T4) have been completely sequenced (Choquer et al., 2007). Unlike many other plant pathogens, B. cinerea occurs year-round and under a wide range of environmental conditions (Nair et al., 1995). The infection / feeding process of B. cinerea is generally described by the following phases: conidia, which are produced on sclerotia of infected plants or plant debris,attach to the surface of a new host and form a germ tube. This develops into an appressorium that facilitates penetration of the host surface. To overcome the host's cuticle barrier, B. cinerea also secretes cell wall-degrading enzymes (CWDEs). Epidermal and mesophyll cells die before the infecting hyphae penetrate. Several metabolites and proteins secreted by the fungus induce symptoms of programmed cell death (PCD) or have been shown to cause cell death (Choquer et al., 2007; Nakajima and Akutsu, 2014). HIGS has already been used to control B. cinerea. The basis for evidence of pathogenicity and virulence genes was obtained through knockout mutants (Nakajima and Akutsu, 2014). This also made it possible to identify potential target genes, some of which are used in the application example described below (ten Have et al., 1998; Li et al., 2019; Liu et al., 2018; Nerva et al., 2020;Qiao et al., 2021; Schumacher et al., 2008; Segmüller et al., 2008; Soulie' et al., 2006; Ren et al., 2018; Yang et al., 2013; Zheng et al., 2000). In addition to HIGS, topical / transient applications of dsRNA have also been considered as an alternative approach (Wang et al., 2016; Weiberg et al., 2013), and some studies have also shown some efficacy in various fungi (McLoughlin et al., 2018; Gebremichael et al., 2021). The current state of science is that the success rate of this method strongly depends on the fungus' potential to uptake external RNA (Qiao et al., 2021). Summary of the invention Analogous to the description above for CMV and M. incognita, esiRNAs / ERNAs and edsRNAs were characterized that reliably exhibit high fungicidal activity against various variants of B. cinerea. From the esiRNAs / ERNAs characterized in this way, other sRNAs or eASOs could also be derived, which can also be used in RNA silencing / RNAi methods or in RNAsilencing / antisense methods can be used against M. incognita. Detailed description of the invention The object of the invention is achieved by a nucleic acid for protecting plants against the plant pathogens Cucumber mosaic virus, Meloidogyne incognita and Botrytis cinerea, wherein a. the nucleic acid is a small interferring RNA (siRNA) made up of completely or partially complementary nucleic acids, consisting of 21, 22, 23 or 24 base pairs and containing two single-stranded RNAs selected from a guide strand and a passenger strand, wherein the guide strand and the passenger strand are selected from the group consisting of the nucleic acids with SEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, 47-51, 53, 55-66, 69-70, 73, 75-86, 89-90, 93-120, 124, 126-132, 134-138, 140-150, 154, 156-162, 164- 168 and 170-180; or b. the nucleic acid is an siRNA according to group a., wherein at least one of the single-stranded RNAs is selected from a guide strand and apassenger strand, has changes at 1 to 7 positions of the nucleotide sequence; or c. the nucleic acid is a small RNA (sRNA) selected from an siRNA and a micro RNA (miRNA), the RNA double strand of which consists of complementary or partially complementary nucleic acids from group a. and / or group b.; or d. the nucleic acid is a double-stranded RNA which contains nucleotide sequences of at least two siRNAs or sRNAs from groups a, b or c.; or e. the nucleic acid is a single-stranded DNA which consists of 12 to 25 nucleotides and which contains a sequence of 12 or more nucleotides which are homologous (deoxyribonucleotides instead of ribonucleotides) to one of the nucleotide sequences of the single-stranded RNAs selected from a guide strand and a passenger strand from groups a. or b.; or f. the nucleic acid is a single-stranded DNA according to group e. which has changes at 1 to 7 positions of the nucleotide sequence; wherein the nucleic acidProtection from plant pathogens is provided with a method for the targeted identification of effective small interfering RNAs (esiRNAs / ERNAs) and sRNAs derived therefrom, as well as eASO (effective antisense DNA oligonucleotides) of different lengths, collectively referred to as effective nucleic acids (eNAs), comprising the steps of (i) an RNA that has been selected as a target for RNA silencing (RNAi) is produced by in vitro transcription and converted into small interfering RNAs (siRNAs) in cytoplasmic extracts of plant cells by the endogenous Dicer-like proteins (DCL); (ii) a DCL-generated siRNA pool is formed from the RNA used, and the siRNAs contained in this pool are determined by RNA-seq analysis; (iii) a messenger RNA (mRNA) of an Argonaute (AGO) protein synthesized by in vitro transcription is added to the cytoplasmic plant cell extract, the mRNA being constructed in such a way that it is suitable for thethe relevant AGO protein is encoded with a tag; (iv) AGO protein molecules are formed via in vitro translation, which form RNA-induced silencing complexes (RISC) complexes with the DCL-generated siRNAs present; (v) siRNA-loaded AGO / RISC is immunoprecipitated from the BYL via the tag, and the bound siRNA guide strands are determined by RNA-seq analysis; (vi) siRNAs that are enriched in AGO / RISC are identified by comparing the RNA-seq data with those from step (ii); (vii) are then synthetically produced and tested for functionality in a slicer assay with labeled target RNA, and (viii) esiRNAs / ERNAs are identified in this way and sRNAs derived therefrom, as well as eASOs, collectively referred to as eNAs, are determined. characterized in that I. for the formation of the RISC in step (vii) in a reaction solution containing 50% (v / v) BYL, 0.5 pmol of the mRNA of the AGO protein to be used in the presence of 10-100 nM of the syntheticcharacterizing siRNA and a 10-fold excess (0.1-1 µM) of a competitor siRNA (e.g. siR gf698: guide and passenger strand selected from the group consisting of SEQ ID NO: 205, 206, 207, and 208; Iki et al., 2010); II. after an incubation time of 2.5 h at 25 °C per reaction in step I. 3.4 pmol of a non-specific mRNA (e.g. encoding the firefly luciferase protein, SEQ ID NO: 209; Schuck et al., 2013) as further competitor RNA and 10 fmol of the target RNA, whereby the target RNA is labeled, are added and the reactions are incubated again for 15 min at 25 °C; III. During incubation in step II, the target RNA is cleaved by the formed AGO / RISC; IV. After gel electrophoresis of the extracted RNA, the quantity of target RNA remaining compared to a control reaction (carried out without siRNA) or the resulting cleavage products is quantified by measuring the band intensities (ImageQuantTL orImageJ); V. the classification as esiRNA / ERNAs is carried out based on the measured cleavage activity (slicer activity) of the RISC formed with this siRNA on the target RNA; VI. esiRNA / ERNA are selected that endonucleolytically convert at least 25% or more of the quantity of target RNA originally used in process step II into cleavage products; and VII. optionally, other sRNAs and eASOs are derived from the sequence of esiRNAs / ERNAs identified in this way. BYL in step I. preferably has a defined protein quantity and translation activity: The protein quantity is determined using the classic Bradford assay (Wikipedia) and should be 7-12 mg / ml extract (Gursinsky et al., 2009). The translation activity is determined under translation conditions with 85 fmol of firefly luciferase mRNA: The measurable activity of the luciferase translated under these conditions should be in the range of at least 106 RLU (relative light units)of a converted substrate (e.g., luciferol; Wikipedia) (Gursinsky et al., 2009; Schuck et al., 2013; Gago-Zachert et al., 2019). The quantity of siRNA to be tested used in step I. is preferably adjusted to the activity of the respective AGO protein with the siRNA siR gf698 (guide and passenger strand selected from the group consisting of SEQ ID NO: 205, 206, 207, and 208) on its mRNA target, encoding GFP (green fluorescent protein): The cleavage activity measurable with siR gf698 and the GFP mRNA target in the slicer assay is usually 90%: This means that 90% of the quantity of target RNA used is converted to cleavage products. The target RNA in step II. can be labeled using any means known to the person skilled in the art. For example, the target RNA may have a fluorescent marker or be radioactively labeled. Preferably, the target RNA is radioactively labeled in step II. esiRNAs / ERNAs that have a cleavage efficiency of at least 25%in vitro (Step VI), exhibit a clearly measurable antipathogenic effect in vivo compared to control siRNAs (see working examples below and Tables 1, 2, and 7). The invention thus advantageously provides eNAs (effective nucleic acids) that can be used in RNA silencing / RNAi or RNA silencing / antisense methods as active ingredients against various variable plant pathogens. esiRNAs / ERNAs that have a cleavage efficiency of at least 25% or more in vitro are, for example, siRNAs of group a., which consist of 21, 22, 23 or 24 nucleotides and contain two nucleic acids selected from a guide strand and a passenger strand, which are selected from the group consisting of the nucleic acids with SEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, 47-51, 53, 55-66, 69-70, 73, 75-86, 89-90, 93-120, 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180. Preferred according to the invention are esiRNAs / ERNAs,which have a cleavage efficiency of at least 50% or more in vitro. esiRNAs / ERNAs that have a cleavage efficiency of at least 50% or more in vitro are, for example, siRNAs of group a., which consist of 21, 22, 23 or 24 nucleotides and contain two nucleic acids, selected from a guide strand and a passenger strand, which are selected from the group consisting of the nucleic acids with SEQ ID NO: 1, 2, 4, 6-11, 14- 17, 21-25, 27, 28, 30, 32-37, 40-42, 47-51, 55-66, 75-86, 93-120, 128-132, 134, 135, 138, 140-150, 158- 162, 164, 165, 168, and 170-180 are selected. More preferred according to the invention are esiRNAs / ERNAs that have a cleavage efficiency of at least 75% or more in vitro. esiRNAs / ERNAs that have a cleavage efficiency of at least 75% or more in vitro are, for example, siRNAs of group a., which consist of 21, 22, 23 or 24 nucleotides and contain two nucleic acids selected from a guide strand and a passenger strand, which consist ofthe group consisting of the nucleic acids with SEQ ID NO: 2, 4, 6, 8, 10, 11, 14-16, 21, 22, 24, 25, 28, 30, 32, 34, 36, 37, 40-42, 47, 48, 50, 51, 55, 60-63, 65, 69, 75, 80-83, 85, 89, 94-101, 103-106, 108-115, 117-120, 130, 134, 140, 143, 145, 146, 160, 164, 170, 173, 175, and 176. Particularly preferred according to the invention are esiRNAs / ERNAs which have a cleavage efficiency of at least 90% or more in vitro. esiRNAs / ERNAs that have a cleavage efficiency of at least 90% or more in vitro are, for example, siRNAs of group a., which consist of 21, 22, 23 or 24 nucleotides and contain two nucleic acids, selected from a guide strand and a passenger strand, which are selected from the group consisting of the nucleic acids with SEQ ID NO: 4, 6, 10, 11, 14-16, 21, 22, 24, 30, 32, 37, 40-42, 47, 48, 50, 61, 81, 96, 97, 99, 101, 104-106, 110, 111, 113, 115, and 118-120. Particularly preferred according to the invention are esiRNAs / ERNAs thathave a cleavage efficiency of at least 95% or more in vitro. esiRNAs / eRNAs that have a cleavage efficiency of at least 95% or more in vitro are, for example, siRNAs of group a., which consist of 21, 22, 23 or 24 nucleotides and contain two nucleic acids selected from a guide strand and a passenger strand, which are selected from the group consisting of the nucleic acids with SEQ ID NO: 6, 10, 32, 36, 97 and 11. The sequences of the guide strands and the associated passenger strands are shown in Tables 1, 2, 7 and 8, respectively. Process steps (i) to (vii) are described in WO2019001602 A1. WO2019001602 A1 is incorporated herein by reference. Process steps I. to VII. are novel and based on the embodiments of the present application. According to group a. the nucleic acid is an siRNA consisting of 21, 22, 23 or 24 nucleotides and two nucleic acids selected from a guide strand and a passenger strand,wherein the guide strand and the passenger strand are selected from the group consisting of the nucleic acids with SEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, 47-51, 53, 55-66, 69-70, 73, 75-86, 89-90, 93- 120, 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180. The single-stranded nucleic acids with the SEQ ID NO: 1-4, 6-11, 14-17, 21-26, 27-30, 32-37, 40-43, 47-51, 53, 55-66, 69-70, 73, 75-86, 89-90, 93-120, 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180 are components (single-stranded components such as guide strands and passenger strands) of the effectively active nucleic acids newly identified within the scope of the invention, which in the form of small RNAs, sRNAs, in RNA silencing / RNAi methods in plant protection as active substances against various, variable plant pathogens. According to group b., the nucleic acid of the invention is an siRNA comprising two single-stranded RNAs selected from a guide strand and apassenger strand, according to group a., wherein the guide strand and / or the passenger strand have changes at 1 to 7 positions of the nucleotide sequence. The nucleic acids of group b. thus represent variants of the nucleic acids of group a. "Change" in the sense of the invention means "base exchange", i.e., that a base selected from adenine (A), uracil (U), guanine (G), and cytosine (C) can be exchanged for any of the other bases. Such base exchanges can occur at 1 to 7 positions of the nucleotide sequence of a nucleic acid of group a. The base exchanges are preferably independent of each other at each position, i.e., each of the 1 to 7 positions of the nucleotide sequence of a nucleic acid of group a. can be exchanged independently of each other by any of the other bases. According to group c., the nucleic acid of the invention is a small RNA (sRNA, such as a small interfering RNA, siRNA, or such as a micro RNA, miRNA).whose RNA double strand consists of fully complementary or partially complementary nucleic acids of group a and / or group b. Small interfering RNAs, abbreviated as siRNAs, are short, double-stranded, non-coding ribonucleic acid molecules 20 to 25 base pairs long that are phosphorylated at the 5' end and have a 2-nucleotide (nt) long, single-stranded overhang at the 3' end. As described above, siRNAs are generated under natural conditions in a cell from double-stranded regions of RNA molecules, usually foreign RNA that is not native to the cell; however, they can also be used in synthetic form for targeted RNA silencing / RNAi techniques. Except for the mentioned 3' overhang, the two constituent single strands of an siRNA are completely base-paired (i.e., over the entire length of the RNA) via complementary base pairing (usually adenine (A) with uracil (U) and guanine (G) with cytosine (C)) and form an RNA duplex.During the RNA silencing / RNAi process, one of the two single-stranded components of the siRNA associates with complementary single-stranded regions (target sites) of other ribonucleic acid molecules, referred to here as target RNAs. These are predominantly the cognate RNAs from which the siRNAs were originally generated. The function of the target RNAs can thus be inhibited or modulated in various ways. In eukaryotes, for example, siRNAs can suppress the replication of pathogens such as viruses or the expression of cellular genes at the post-transcriptional level. MicroRNAs, abbreviated to miRNAs, are short, non-coding ribonucleic acids that are encoded by the cellular genome in the form of precursor molecules. After transcription and processing, complementary regions of the miRNA, which usually consist of 21 to 23 nt long RNA strands, form double strands through base pairing. In contrast to siRNAs, these double-stranded regions in miRNAs can be replaced by single-strandedRegions may be interrupted in the form of so-called "mismatches" (affecting individual nucleotides) and / or "loops" and / or "bulges" (affecting multiple nucleotides). Like siRNAs, miRNAs inactivate or modulate the function of a target RNA through the RNA silencing / RNAi process by binding (hybridizing) to completely or incompletely complementary regions of that RNA. Accordingly, miRNAs play a central role in the post-transcriptional regulation of cellular gene expression and, like siRNAs, can also be used to artificially modulate cellular gene expression. As already explained above, two nucleic acid strands are said to be "complementary" if their nucleotides can base pair with each other. Originally, the pairing rule for DNA was defined according to the classical pairing rule of nucleotide bases according to Watson and Crick, where adenine (A) from one nucleic acid strand is linked via hydrogen bonds with thymine (T) from the other nucleic acid strand and guanine (G)from one nucleic acid strand with cytosine (C) from the other nucleic acid strand can interact (base pair). As a result, DNA forms a double strand, with each strand being, so to speak, the negative version of the other strand. RNA molecules can form double strands according to a similar pattern, i.e., via hydrogen bonds of adenine (A) with uracil (U) (RNA molecules do not contain thymine, but uracil) and of guanine (G) with cytosine (C), but also via other base pairings not described here. These double strands can be formed intermolecularly, i.e., between different RNA molecules, or intramolecularly, i.e., within an RNA molecule. As explained above, double-stranded regions of an RNA can comprise many nucleotide building blocks (possibly hundreds or thousands) and thus a corresponding number of base pairs. In this case, the term "dsRNA" is used, as explained above. Intramolecularly formed double strands are an essential determinantthe formation of complex structures within an RNA. It is also possible for complementary RNA and DNA molecules to form double strands, so-called DNA:RNA hybrids or DNA:RNA heteroduplexes. “Completely complementary” generally defines two nucleic acid strands that can form base pairs over their entire length and over their entire number of nucleotide building blocks, thus forming a double strand. As explained, functional siRNAs and other sRNAs have overhangs of one or more nucleotides at the termini. Likewise, dsRNAs can have overhangs of one or more nucleotides at the termini or spacers (see definition above). The term “completely complementary” within the meaning of the invention refers accordingly to the nucleotide sequences of the nucleic acids of groups a., b., c. and d., excluding these overhangs or spacers. “Partially complementary” in the sense of the invention defines nucleic acid strands that are not completely complementaryand therefore cannot form base pairs across their entire length and total number of nucleotide building blocks. Double-stranded regions of these nucleic acids are interrupted by single-stranded regions such as mismatches, loops, and / or bulges. Particularly preferred in group c. is when the nucleic acid is an siRNA whose RNA duplex consists of completely complementary nucleic acids from group a. and / or group b. In the context of the invention, these are siRNAs that have been newly identified via “eNA screens” and, according to the above definition, induce the hydrolysis of 25% or more, preferably 50% or more, more preferably 75% or more, particularly preferably 90% or more, especially preferably 95% or more of the quantity of target RNA used in a standardized and stringently conducted in vitro slicer assay in the corresponding AGO / RISC, thus being classified as esiRNAs / ERNAs (effectively active siRNAs) andcan be used in RNA silencing / RNAi methods in plant protection as active ingredients against variable plant pathogens. Also preferred in group c. is when the nucleic acid is an sRNA, such as a miRNA, whose RNA double strand consists of partially complementary nucleic acids from group a. and / or group b. These are sRNAs whose nucleotide sequences can be derived from the above-mentioned esiRNAs / eRNAs and which can also be used in RNA silencing / RNAi methods in plant protection as active ingredients against variable plant pathogens. According to group d., the nucleic acid of the invention is a double-stranded RNA which contains nucleotide sequences of at least two siRNAs or sRNAs from group c. These are double-stranded ribonucleic acids (edsRNAs; effectively effective double-stranded RNAs) that have been designed and constructed in a completely new way within the scope of the invention and which contain the nucleotide sequences of identified esiRNAs / ERNAs orother sRNAs derived therefrom, such as miRNAs, and which can be used in RNA silencing / RNAi methods in plant protection as active ingredients against variable plant pathogens. For the purposes of the invention, this means that the RNA double strand of these nucleic acids contains nucleotide sequences of at least two nucleic acids from group a., b. or c. In a preferred embodiment, a nucleic acid from group d. contains the nucleotide sequences of at least two small RNAs (sRNAs, such as a small interfering RNA, siRNA, or e.g. a micro RNA, miRNA), whose RNA double strand consists of completely or partially complementary nucleic acids from group a. and / or group b. In a further preferred embodiment, a nucleic acid from group d. has the nucleotide sequences of at least two siRNAs whose RNA double strand consists of completely complementary nucleic acids from group a. and / or group b. In a further preferred embodimenta nucleic acid from group d. contains the nucleotide sequences of at least two sRNAs, such as miRNAs, whose RNA double strand consists of partially complementary nucleic acids from group a. and / or group b. In a further preferred embodiment, a nucleic acid from group d. contains the nucleotide sequences of two, three, four, five... up to an infinite number of siRNAs and / or sRNAs from groups a., b. or c.. Preferably, a nucleic acid from group d. contains the nucleotide sequences of 2 to 100 siRNAs and / or sRNAs from groups a., b. or c. It is particularly preferred if the nucleic acid from group d. which contains nucleotide sequences of 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40 or 2 to 30 siRNAs and / or sRNAs of groups a., b. or c. It is particularly preferred if the nucleic acid of group d. contains the nucleotide sequences of 2 to 20 or 2 to 10 siRNAs and / or sRNAs of groups a., b. or c. In another embodiment of theAccording to the invention, it is preferred if the nucleic acid of group d. contains the nucleotide sequences of more than 2 siRNAs and / or sRNAs of groups a., b., or c., i.e. at least 3, 4, 5, 6, 7, 8, 9, 10 or more (up to 100) sRNAs of groups a., b., or c. According to group e., the nucleic acid is a single-stranded DNA containing a sequence of 12 or more nucleotides that is homologous (deoxyribonucleotides instead of ribonucleotides) to one of the nucleotide sequences of the single-stranded RNAs of groups a. or b. Sequence homology is the similarity of nucleotide or amino acid sequences due to identical chemical building blocks in more or less large sub-regions of the molecular chains of peptides, RNA, or DNA. Completely identical molecular chains represent 100% sequence homology. In the present case, homology means 100% sequence homology over 12 or more nucleotides contained in the single-stranded DNA to one of the single-stranded RNAs of groups a.or b., wherein the DNA consists of deoxyribonucleotides and the RNA of ribonucleotides. Group e. comprises the antisense deoxyribonucleic acid (DNA) oligonucleotides (ASOs) provided by the invention, the sequence of which can be derived from the esiRNAs / ERNAs identified within the scope of the invention. In analogous terminology to the term esiRNAs / ERNAs, the ASOs derived from the sequences of the single-stranded RNA components of the esiRNAs / ERNAs of groups a. and b. are referred to here as eASOs. eASOs contain DNA sequences homologous to the single-stranded RNA components of the esiRNAs / ERNAs of groups a. and b. (i.e., deoxynucleotides instead of ribonucleotides; thymidine instead of uridine) and can thus also hybridize to the respective target sites in the a-sites of the target RNAs via appropriate base pairing and become active. The functionality of ASOs is similar but not identical to that of sRNAs. As detailed above, ASOs bind via base pairing(hybridization) to completely or partially complementary regions (target sites) of a target RNA. However, the inactivating effect of ASO on a target RNA does not occur via RNAi as with sRNAs, but via antisense processes, e.g. inhibition of translation or endonucleolytic degradation by RNases of the RNase H type (see above). According to group f., the nucleic acid of the invention is a single-stranded DNA which has changes at 1 to 7 positions of the nucleotide sequence. The nucleic acids of group f. thus represent variants of the nucleic acids of group e. “Change” in the sense of the invention means “base exchange”, e.g. that a base selected from adenine (A), thymine (T), guanine (G) and cytosine (C) can be exchanged for any of the other bases. Such base exchanges can occur at 1 to 7 positions of the nucleotide sequence of a nucleic acid of group e. The base exchanges are preferably independent at each position,i.e., each of the 1 to 7 positions of the nucleotide sequence of a nucleic acid of group e can be independently exchanged by any of the other bases. According to one aspect of the invention, the nucleic acid is a nucleic acid for protecting plants against the plant pathogen Cucumber mosaic virus (CMV). Preferably, the nucleic acid for protecting against CMV is a nucleic acid directed against a target RNA of CMV. It is particularly preferred if the nucleic acid for protecting against CMV is a nucleic acid directed against a target RNA of CMV, wherein the target RNA of CMV is selected from the target RNAs with SEQ ID NO: 189 and 190. A nucleic acid directed against a target RNA of CMV selected from SEQ ID NO: 189 and 190 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 1 to 92is selected. The CMV target RNA with SEQ ID NO: 189 is hereinafter also referred to as “CMV RNA 2”. The CMV target RNA with SEQ ID NO: 190 is hereinafter also referred to as “CMV RNA 3”. As described in Application Example 1, nucleic acids against CMV RNA 2 (SEQ ID NO: 189) were identified, a significant proportion of which induces efficient hydrolysis (at least 25%, preferably at least 50%, more preferably at least 75%, particularly preferably at least 90%, especially preferably at least 95% of the quantity originally used in the respective assay) of the target RNA (CMV RNA 2) in the slicer assay and protects plants against CMV infections (see also Figures 2 - 4). The screening was performed with both AGO1 (L version; Gursinsky et al., 2015) and AGO2 from Nicotiana benthamiana (Nb). As described in Application Example 1, nucleic acids were identified against CMV RNA 3 (SEQ ID NO: 190),Some of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (CMV RNA 3) in the slicer assay and protect plants against CMV infections (see also Figures 5, 6). The screening was carried out with both AGO1 (L version; Gursinsky et al., 2015) and AGO2 from Nicotiana benthamiana (Nb). A nucleic acid directed against a target RNA CMV RNA 2 of CMV with SEQ ID NO: 189 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of nucleic acids with SEQ ID NO: 1 to 52. Particularly suitable is a nucleic acid directed against a target RNA CMV-RNA 2 of the CMV with SEQ ID NO: 189, a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with theSEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, and 47-51. A nucleic acid directed against a target RNA CMV-RNA 2 of the CMV with SEQ ID NO: 189 and identified in the screening with AGO1 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 1 to 12 and SEQ ID NO: 27 to 38, preferably with SEQ ID NO: 1 to 4, 6 to 11, 27 to 30, and 32 to 37. A nucleic acid directed against a target RNA CMV-RNA 2 of the CMV with SEQ ID NO: 189 and identified in the screening with AGO2 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 13 to 26 and SEQ ID NO: 39 to 52, preferably with SEQ ID NO: 14 to 17, 21 to 25, 40 to 43 and 47to 51. A nucleic acid directed against a target RNA CMV-RNA 3 of the CMV with SEQ ID NO: 190 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 53 to 92. A nucleic acid directed against a target RNA CMV-RNA 3 of the CMV with SEQ ID NO: 190 and identified in the screening with AGO1 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 53-55, 59, 63, 64, 66, 67, 70-75, 79, 83, 84, 86, 87, 90-92, preferably with SEQ ID NO: 53, 55, 59, 63, 64, 66, 70, 73, 75, 79, 83, 84, 86 and 90. A nucleic acid directed against a target RNA CMV-RNA 3 of CMV with SEQ ID NO: 190 and identified in the screening with AGO2,is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NOs: 56 to 58, 60 to 62, 65, 68, 69, 76 to 78, 80 to 82, 85, 88, 89, preferably with SEQ ID NOs: 56-58, 60-62, 65, 69, 76-78, 80-82, 85 and 89. According to a further aspect of the invention, the nucleic acid is a nucleic acid for protecting plants against the plant pathogen Meloidogyne incognita. Preferably, the nucleic acid for protection against Meloidogyne incognita is a nucleic acid directed against a target RNA of Meloidogyne incognita. It is particularly preferred if the nucleic acid for protection against Meloidogyne incognita is a nucleic acid directed against a target RNA of Meloidogyne incognita, wherein the target RNA of Meloidogyne incognita is selected from the target RNAs with SEQ ID NO: 191, 192 and 193. The target RNA of Meloidogyne incognitawith SEQ ID NO: 191 is hereinafter also referred to as "SPF". The target RNA of Meloidogyne incognita with SEQ ID NO: 192 is hereinafter also referred to as "INT". The target RNA of Meloidogyne incognita with SEQ ID NO: 193 is hereinafter also referred to as "ACT". As described in Application Example 3, nucleic acids against SPF (SEQ ID NO: 191) were identified, a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (SPF) in the slicer assay and in vivo after uptake by the nematodes and protect plants against Meloidogyne incognita infections (see also Figure 16 A and B). The screening was carried out using the AGO2 protein from Nicotiana benthamiana (Nb). As described in Application Example 3, nucleic acids were identified against INT (SEQ ID NO: 192), a significant proportion of which were detected in the slicer assay and inIn vivo, after uptake into the nematodes, it induces efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (SPF) and protects plants against Meloidogyne incognita infections (see also Figure 17 A and B). The screening was carried out using the AGO2 protein from Nicotiana benthamiana (Nb). As described in Application Example 3, nucleic acids against ACT (SEQ ID NO: 193) were identified, a significant proportion of which induced efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (SPF) in the slicer assay and in vivo after uptake into the nematodes and protected plants against Meloidogyne incognita infections (see also Figure 17 A and B). The screening was carried out using the AGO2 protein from Nicotiana benthamiana (Nb). A nucleic acid directed against a target RNA of Meloidogyne incognita selected from SEQ ID NO: 191, 192 and 193is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of nucleic acids with SEQ ID NO: 93 to 120. A nucleic acid directed against a target RNA of Meloidogyne incognita SPF with SEQ ID NO: 191 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of nucleic acids with SEQ ID NO: 93 to 95 and 107 to 109. A nucleic acid directed against a target RNA of Meloidogyne incognita INT with SEQ ID NO: 192 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NOs: 96 to 99, 110 to 113. A nucleic acid directed against a target RNA of Meloidogyne incognita ACTwith SEQ ID NO: 193 is preferably a ribonucleic or deoxyribonucleic acid that contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NOs: 100 to 106, 114 to 120. According to a further aspect of the invention, the nucleic acid is a nucleic acid for protecting plants against the plant pathogen Botrytis cinerea. Preferably, the nucleic acid for protecting against Botrytis cinerea is a nucleic acid directed against a target RNA of Botrytis cinerea. It is particularly preferred if the nucleic acid for protection against Botrytis cinerea is a nucleic acid directed against a target RNA of Botrytis cinerea, wherein the target RNA of Botrytis cinerea is selected from the target RNAs with SEQ ID NO: 194, 195, 196, 197, 198 and 199. The target RNA of Botrytis cinerea with SEQ ID NO: 194 is hereinafter also referred to as "VDS". The target RNA ofBotrytis cinerea with SEQ ID NO: 195 is hereinafter also referred to as "DCTN". The target RNA of Botrytis cinerea with SEQ ID NO: 196 is hereinafter also referred to as "SAC". The target RNA of Botrytis cinerea with SEQ ID NO: 197 is hereinafter also referred to as "ERG". The target RNA of Botrytis cinerea with SEQ ID NO: 198 is hereinafter also referred to as "EF". The target RNA of Botrytis cinerea with SEQ ID NO: 199 is hereinafter also referred to as "CHS". As described in Application Example 4, nucleic acids were identified against VDS (SEQ ID NO: 194), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (VDS) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed using the AGO1 protein from Colletotrichum graminicula.(Cg). As described in Application Example 4, nucleic acids were identified against DCTN (SEQ ID NO: 195), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (DCTN) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed using the AGO1 protein from Colletotrichum graminicula (Cg). As described in Application Example 4, nucleic acids were identified against SAC (SEQ ID NO: 196), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (SAC) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed with the AGO1 protein from Colletotrichum graminicula (Cg).As described in Application Example 4, nucleic acids were identified against ERG (SEQ ID NO: 197), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (ERG) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed using the AGO1 protein from Colletotrichum graminicula (Cg). As described in Application Example 4, nucleic acids were identified against EF (SEQ ID NO: 198), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (ERG) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed with the AGO1 protein from Colletotrichum graminicula (Cg). As described in Application Example 4As described, nucleic acids were identified against CHS (SEQ ID NO: 199), a significant proportion of which induce efficient hydrolysis (at least 25% of the quantity originally used in the respective assay) of the target RNA (CHS) in the slicer assay and protect plants against Botrytis cinerea infections (see also Figures 18 and 19 A and B). The screening was performed using the AGO1 protein from Colletotrichum graminicula (Cg). A nucleic acid directed against a target RNA of Botrytis cinerea selected from SEQ ID NOs: 194, 195, 196, 197, 198 and 199 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NOs: 121 to 180, preferably with SEQ ID NOs: 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180. A nucleic acid directed against a target RNA of Botrytis cinerea VDS withof SEQ ID NO: 194 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 121, 122 and 151, 152. A nucleic acid directed against a target RNA of Botrytis cinerea DCTN with SEQ ID NO: 195 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NO: 123-131 and 153-161, preferably from SEQ ID NO: 124, 126-131, 154 and 156-161. A nucleic acid directed against a target RNA of Botrytis cinerea SAC with SEQ ID NO: 196 is preferably a ribonucleic or deoxyribonucleic acid containing or consisting of at least one nucleic acid selected from the group consisting of the nucleic acids with SEQ ID NOs: 132-140 and 162-170,preferably selected from SEQ ID NOs: 132, 134-138, 140, 162, 164 to 168 and 170. A nucleic acid directed against a target RNA of Botrytis cinerea ERG with SEQ ID NO: 197 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid which is preferably selected from the group consisting of the nucleic acids with SEQ ID NOs: 141 to 149, 171 to 179. A nucleic acid directed against a target RNA of Botrytis cinerea EF with SEQ ID NO: 198 is preferably a ribonucleic or deoxyribonucleic acid which contains or consists of at least one nucleic acid which is preferably selected from the group consisting of the nucleic acids with SEQ ID NOs: 150 and 180. In a further aspect of the invention, the nucleic acid is a double-stranded RNA, wherein this double-stranded RNA preferably contains nucleotide sequences consisting of so-called “pseudo-siRNA sequences” and sequences ofat least two and a maximum of an infinite number of sRNAs according to group c. The double-stranded RNA preferably contains nucleotide sequences which consist of pseudo-siRNA sequences and sequences of 2 to 10,000 sRNAs according to group c. It is particularly preferred if the double-stranded RNA contains nucleotide sequences which consist of pseudo-siRNA sequences and sequences of 2 to 5,000 or 2 to 2,500 sRNAs according to group c. It is very particularly preferred if the double-stranded RNA contains nucleotide sequences which consist of pseudo-siRNA sequences and sequences of 2 to 1,000, 2 to 500, 2 to 250, 2 to 100 or 2 to 50 sRNAs according to group c. These are the nucleic acids of group d., “edsRNAs”, as described above and in application example 2. A so-called “pseudo-siRNA sequence” or “pseudo-siRNA” in the sense of the invention is a double-stranded ribonucleotide sequence of any composition which, according to the planned processing of the respectiveedsRNA is 21, 22, 23, or 24 nt long (see also Application Example 2). The name "pseudo-siRNA sequence" or pseudo-siRNA was chosen to express the fact that it is a double-stranded ribonucleotide sequence with a similar structure to siRNA, but does not actually function as an siRNA, but rather has other functions described below. Pseudo-siRNA sequences are placed at the termini of a double-stranded RNA (edsRNA) constructed according to the invention. Through their presence, they force the Dicer or DCLs active on this RNA into "clocked processing." As described in detail in Example 2, timed processing means that, depending on the position and length of the pseudo-siRNA sequences and the activity of the Dicer / DCLs involved, the endonucleolytic cleavages of the double-stranded RNA are carried out in such a way that the preferentially generated sRNAs have the same length as the pseudo-siRNAs.That this occurs in this way was demonstrated according to the invention (Figure 14). Pseudo-siRNA sequences can also contain functional elements within the meaning of the invention: These can be elements that are important for the transcription and processing of the respective RNA. These can be, for example, regions of a transcription promoter or terminator; but they can also be transport signals or parts of a ribozyme (ribozymes), which generates the correct 5' or 3' end of the respective RNAs by self-splicing (self-catalyzed cleavage). Transcription promoters are signal sequences in a DNA double strand, one strand of which (template strand) codes for an RNA molecule. The transcription promoter is recognized by a DNA-dependent RNA polymerase complex and, due to the association with this promoter sequence, the RNA polymerase complex can initiate the transcription (synthesis) of an RNA molecule whose nucleotide sequenceis complementary to the DNA template strand. Transcription activators that bind to the RNA polymerase complex and / or other DNA sequences can specifically induce transcription. Examples of transcription promoters are viral promoters such as the T7 phage promoter (T7 promoter). Examples of cellular promoters are the Pol I and Pol II promoters. Other examples of common viral promoters are: T3 promoter (T3 phage promoter), SP6 promoter (SP6 phage promoter), CMV promoter (human cytomegalovirus promoter). Other examples of common cellular promoters are: GAL promoters, LAC4 promoters, actin promoter, Pol III promoter. Other suitable transcription promoters are known to the person skilled in the art. Transcription terminators are nucleotide sequences that, like transcription promoters, are encoded by RNA-encoding DNA. When these sequences are transcribed by the RNA polymerase complex, they lead to the formation ofProtein-RNA complexes that cause the RNA polymerase complex to terminate transcription. An example of a transcription terminator is the transcription terminator of vesicular stomatitis virus (VSV). Other suitable transcription terminators are known to those skilled in the art. Transport signals in RNA molecules cause the binding of proteins that enable the targeted transport of these RNA molecules into or out of specific cellular compartments. One example is nuclear RNA export signals, which enable the export of RNA molecules from the cell nucleus into the cell cytoplasm. Other transport signals are known to those skilled in the art. Ribozymes are catalytically active RNA molecules that, like enzymes, catalyze chemical reactions. Examples include hammerhead (HH) ribozymes (Meyer and Masquida 2014) or the hepatitis delta virus (HDV) ribozyme (Avis et al. 2012). These ribozymes can independently catalyze endonucleolytic cleavage of the RNA molecule,of which they are a component (self-cleavage or self-splicing). The basic principle of the construction of edsRNAs designed according to the invention is thus as follows (see also Figures 8 - 11): The sequence contains at least one pseudo-siRNA sequence, which, as explained, enables timed processing by Dicer / DCLs. In addition, the edsRNA sequence contains a number of 5' to 3' "lined up" sequences of esiRNAs / ERNAs or other sRNAs derived from esiRNAs / ERNAs, such as miRNAs. These sequences can originate from various "eNA screens," and accordingly, the esiRNA / ERNAs or sRNAs derived from them can be active in various AGO / RISCs. The esiRNA / ERNAs or their derived sRNAs that constitute an edsRNA can thus be directed against different target RNAs originating from one or different organisms. The generation of an edsRNA can occur in two ways: From two independently transcribedcomplementary RNA molecules or from a transcribed RNA molecule containing two complementary subregions (Figure 8). In the second case, the two complementary subregions of the transcribed RNA are connected by a spacer, forming a hairpin. The spacer is a sequence of any composition with a minimum length of 4 nucleotides (see definition above), which, for the specific purpose of edsRNA construction, may contain functional regions such as ribozymes (such as HH or HDV ribozymes), transcription promoters or transcription terminators, transport signals, or splice sites. Splice sites are sequence motifs in regions of precursor RNA molecules, such as introns, that are recognized by the splicing machinery of a cell. The splicing machinery catalyzes the complete or partial removal of the intron sequence. Through the presence of these elements, the spacer sequence serves, in addition to the function of the twocomplementary single-stranded components of a dsRNA, for other purposes: If it contains splice sites, for example, the spacer can be shortened during the expression of the RNA in vivo by the splicing machinery of the cell. Since the spacer, in contrast to the double-stranded RNA regions, is sensitive to ribonucleases (such as the single-strand-specific RNases T1 or A) present in the cell, this sequence can also be completely removed by these RNases (see also Figure 8). Examples of spacers are sequences of introns from mRNA precursor molecules ("pre-mRNAs"), which contain all the recognition sequences necessary for splicing. These recognition sequences are known to the person skilled in the art. The transcription of the RNAs can occur in vitro or in vivo. The double strand is obtained by hybridization of the complementary RNA strands (Figure 8). Transcription can occur through a variety of promoters (see, for example, Figure 11).Transcription termination can occur through any type of transcription terminator (such as the VSV transcription terminator, see Figure 11 for an example). Depending on the type of generation, the termini of the edsRNAs are either blunt or they contain an overhang (-Ü) (Figure 15). They can be generated in different ways, e.g., via "run-off transcription" ("running off the DNA template by the RNA polymerase complex") or termination of the respective RNA polymerase complex via a transcription terminator, or through the activity of ribozymes via self-splicing. The sequences of both strands are designed so that the authentic sRNA guide and passenger strand sequences are generated during processing by DCLs. The processing, which predominantly leads to the generation of the constituent esiRNAs / ERNAs or sRNAs derived from them, is determined by the presence of the pseudo-siRNA sequences and the resulting “clocked processing” by the DCLs / Dicerensured (see application example 2 and Figures 8-14). The double-stranded RNA of the invention can thus have blunt ends in one embodiment, and overhanging ends in another embodiment. In a further embodiment of the invention, the double-stranded RNA can contain a spacer. In a further embodiment of the invention, the pseudo-siRNAs and / or spacers in the nucleic acid according to the invention contain elements selected from transcription promoters, transcription terminators, transport signals, splice sites, and ribozymes. In a particularly preferred embodiment of the invention, the double-stranded RNA of the invention is selected from the group consisting of the nucleic acids with SEQ ID NO: SEQ ID NO: 181, 182, 185, 186, and 200 to 204. The functionality and significantly improved protection against pathogens of such novel edsRNAs compared to conventional dsRNAs was demonstrated according to the invention (see, for example,Figures 14 and 15). In a further embodiment, the nucleic acid according to the invention has one or more chemical modifications, wherein the chemical modifications are selected from conjugates such as GalNac, base modifications such as 5-methylcytosine, 2'-sugar modifications such as 2'-O-methyl, 2'-fluoro, 2'-O-methoxyethyl (2'-MOE), cETBNA ((S)-linked ethyl bicyclic), other sugar modifications such as "locked" (LNA) or "unlocked" (UNA), "backbone" modifications such as phosphorothioate (PS) or "peptide nucleic acids" (PNA), and sugar phosphate modifications such as morpholino / PMO (phosphorodiamidate morpholino). Other modifications are known to the person skilled in the art. In a further aspect, the invention relates to a composition comprising at least one, optionally several, nucleic acid(s) of the invention, as described herein. The nucleic acids according to the present invention can be used in transgenic form, e.g. HIGS methods for pathogen control or for targeted,transcriptional and post-transcriptional regulation of gene expression. They are particularly suitable for use in pathogen control in plants / crops. In one embodiment, the invention therefore relates to the use of a nucleic acid or composition according to the invention in plants for the prophylaxis and / or treatment against infestation and / or infections by pathogens, in particular for the prophylaxis and / or treatment against infestation and / or infections by pathogens selected from Cucumber mosaic virus, Meloidogyne incognita and Botrytis cinerea. Transgenic means that the genetic information encoding at least one, optionally several, of the nucleic acid(s) of the invention is stably introduced into the genome of a host organism, preferably a plant, a microorganism or one of the pathogens mentioned, and is produced (expressed) in this organism in an inducible or non-inducible manner via corresponding promoters.If the organism is a plant, the plant can thus be made resistant to infestation and / or infection by one or more of the corresponding pathogens. If this organism is a microorganism such as bacteria or yeast, the corresponding nucleic acid can be produced in these microorganisms. The nucleic acids according to the present invention can also be used in transient (non-transforming) form, e.g. SIGS methods, for pathogen control or for the targeted, transcriptional and post-transcriptional regulation of gene expression. They are particularly suitable for use in pathogen control in plants / crop plants. In one embodiment, the invention therefore relates to the use of a nucleic acid or composition according to the invention in plants for the prophylaxis and / or treatment against infestation and / or infection by pathogens, in particular for the prophylaxis and / or treatment against infestation and / or infection by pathogens selectedfrom CMV, Meloidogyne incognita and Botrytis cinerea. In transient applications, so-called topical / transient applications, one or more nucleic acids of the invention are applied to target organs of a plant, such as leaves, stems or roots. The nucleic acids are then either taken up by the plant, e.g. to inhibit the replication of infecting viruses, or attacking (infesting) pathogens such as nematodes and fungi, take up the nucleic acids via the surface of the plant to be protected, and these then become active in the RNA silencing / RNAi or RNA silencing / antisense mechanism of the respective organisms against essential target RNAs of the pathogens. In one embodiment, the invention accordingly relates to a composition comprising at least one nucleic acid of the invention and optionally one or more carrier substances and / or excipients, which is suitable for administration in / on plants. The composition is preferably aA solution that can be administered directly, e.g., as a nutrient solution or as an aerosol / spray. This makes it particularly easy to prevent or treat diseases in plants / crops. The composition preferably comprises at least one physiologically acceptable carrier, diluent, and / or excipient. The nucleic acids according to the present invention can be contained in a pharmaceutically acceptable carrier, e.g., in a conventional medium, such as an aqueous salt medium or a buffer solution, as a composition for an aerosol / spray. Such a medium can also contain conventional excipients, such as salts for adjusting the osmotic pressure, buffers, preservatives, nanoparticles, and the like. Other suitable compatible carriers are known to the person skilled in the art, for example, from Remington's Practice of Pharmacy, 13th Edition and J. of Pharmaceutical Science & Technology, Vol. 52, No. 5, Sept.-Oct., pp. 238-311.In a particularly preferred embodiment of the invention, the nucleic acids of the invention are used in transgenic or transient form in RNA silencing / RNAi methods, wherein the nucleic acids of the invention are in the form of double-stranded RNA molecules according to group d., characterized in that they are constructed according to claims 8 to 12 and are processed by Dicer or Dicer-like enzymes to the respective sRNAs. Such a use is described in application example 2. The stated objects were achieved by the invention described below and the application examples described. Nucleic acid active substances, esiRNAs / ERNAs and sRNAs and eASOs derived therefrom (eNAs), were newly identified, which are used in various applications (RNA silencing / RNAi or RNA silencing / antisense methods) as active substances in plant protection against the pathogens Cucumber Mosaic Virus, Meloidogyne incognita, or Botrytis cinerea.The invention further relates to the construction of double-stranded ribonucleic acids (edsRNAs; effectively effective double-stranded RNAs) that are constructed from identified esiRNAs / ERNAs and / or sRNAs derived therefrom and that can be used in the RNA silencing / RNAi process as active ingredients against said pathogens in plant protection. The invention is explained in more detail below with the aid of 19 figures, 8 tables, and 4 application examples. They show: Figure 1: Effective esiRNAs / ERNAs and edsRNAs. Left: Schematic representation of an RNA silencing / RNAi process with a natural siRNA pool, which is generated by DCL activity, for example, from a viral dsRNA: The siRNA pool contains only a few esiRNAs / ERNAs (marked with an "e"); the RNA silencing / RNAi is correspondingly inefficient. Middle: RNA silencing / RNAi performed with esiRNAs / ERNAs identified with the eNA screen; the RNA silencing / RNAi is efficient. Right: Sequence information of theIdentified esiRNAs / ERNAs are used to generate edsRNA; RNA silencing / RNAi with these edsRNAs / derived esiRNAs / ERNAs is also efficient. DCL-Dicer-like proteins; AGO-Argonaute proteins; RISC-RNA induced silencing complex. The siRNA guide strand is marked black for conventional siRNAs and red for esiRNAs / ERNAs. Figure 2: Slicer assays with esiRNAs / ERNAs identified against CMV RNA 2 (SEQ ID NO: 189). As described in the application examples, “eNA screens” were performed with CMV RNA 2 (type Fny), here with a double-stranded version of the RNA. In the final step shown here, slicer assays were performed with the obtained siRNA candidates. It is important to note that here, as in all slicer assays shown below, all tested siRNAs were directed against the (+)-oriented target RNA. AGO1 or AGO2 mRNA was translated in the presence of the siRNA to be tested in BYL (Gago-Zachert et al., 2019). The correspondingThe RISCs formed using the described method were programmed with the siRNA to be characterized, and the endonucleolytic hydrolysis of a defined quantity of radiolabeled CMV RNA 2 (target RNA) was detected by gel electrophoresis and autoradiography. Asterisks (*) mark the cleavage products of the target RNA generated by the slicing activity of the AGO / RISC. The cleavage efficiency can be quantified by autoradiographic measurement of the quantity of the originally used target RNA compared to the negative control and the resulting cleavage products (ImageQuantTL; see also Table 1). As described in the text, a newly established standardized and stringent form of the slicer assay was used here, as well as in all figures shown below: The formation of the AGO / RISC with the respective siRNA to be tested (10 nm) was carried out in the presence of a 10-fold excess (100 nM of a non-specific competitor siRNA (“siR gf698”) directed against the mRNAof the green fluorescent protein, GFP) (see also application examples). This standardized and stringently conducted type of slicer assay served the final definition of an esiRNA / ERNA: Those siRNAs that induce AGO / RISC-mediated hydrolysis of at least 25% of the quantity of target RNA originally used in the respective assay in a slicer assay conducted in this way are considered to be efficiently effective - and thus referred to as esiRNAs / ERNAs (see also Table 1). (A) SiRNA candidates from the "eNA screen" tested with AGO1 / RISC. (B) SiRNA candidates from the "eNA screen" with AGO2 / RISC. All identified esiRNAs / ERNAs are summarized in Table 1. (C) Schematic representation of the binding sites of the most efficient siRNAs on CMV RNA 2. Protein-coding regions are shown as gray boxes. The numbers of the siRNA candidates correspond to the designations given below in the figures, tables, and text (with abbreviations siR or siRCV2). Figure 3:Characterization of the protective efficacy of CMV RNA 2-specific esiRNAs / eRNAs in planta. Four- to five-week-old N. benthamiana plants were mechanically inoculated with genomic CMV RNAs 1, 2, and 3, generated from infectious cDNAs, as well as individual synthetic siRNA candidates and monitored for the appearance of CMV-specific symptoms over a period of 35 days (dpi = days post inoculation). (A) Representative images of individual individuals illustrate the differences between asymptomatic and symptomatic plants 35 days after inoculation. The number of plants remaining asymptomatic is indicated. (B) The graph shows the percentage of asymptomatic plants over the entire course of the experiment: The curves with AGO1-specific siRNAs are shown in black, with AGO2-specific siRNAs and the siR gf698 control in gray. The results are from three independent plant experiments. The number ofThe number of plants used is indicated (n = 12-15). As shown, esiRNA / ERNAs protect the plants very efficiently against CMV infection. (C) Agarose gels from an RT-PCR are shown for the detection of viral infection at the RNA level. Leaf discs from asymptomatic and symptomatic plants were taken at 35 dpi, the RNA was extracted, and cDNA was synthesized using reverse transcriptase. Subsequently, a PCR was performed to detect a conserved sequence present in RNAs 1, 2, and 3 of Cucumber mosaic virus. The CMV-specific sequence was amplified from plasmids containing the cDNA sequence of the respective viral RNA (positive control) as well as from samples from symptomatic plants. As can be seen, no PCR product derived from CMV RNA could be obtained from cDNA of asymptomatic plants. The RT-PCR thus confirms the visual-based classification into symptomatic and asymptomatic plants. The numberscorrespond to the numbering of the respective plants from the infection experiment. (–) RT assays (no addition of reverse transcriptase during the reaction) and the "water control" (addition of water instead of cDNA during the PCR reaction) served as negative controls. (M = GeneRuler 100 bp DNA ladder, Thermo Scientific). The numbers of the siRNA candidates correspond to the designations given above and below in the figures, tables, and text (with abbreviation siR or siRCV2). Table 1. esiRNA / eRNA candidates against CMV-RNA 2 (SEQ ID NO: 189). Listed are 21 nt long siRNAs identified from CMV-RNA 2 in the "eRNA screens." The single-stranded guide and complementary passenger strands are listed in each case. The siRNAs were named siRCV (CV for CMV) according to the respective target RNA (CMV RNA 2) and the position of the 5' end of the identified guide strand. The siRNAs were classified using slicer assays as described:The percentage of the respective target RNA cleaved by the esiRNAs / ERNAs in the standardized and stringently performed slicer assays. esiRNAs / ERNAs that were identified in the "eNA screen" according to the definition (see text) are marked in bold: AGO1-selected in black; AGO2-selected in gray. Other siRNAs that were also identified in the screen but do not meet the definition of esiRNAs / ERNAs are shown in normal font. Some of these siRNAs (e.g., siRCV21844 and 2634) served as negative controls in the infection experiments in N. benthamiana, therefore they are included here. The efficiency in protection experiments with N. benthamiana is given for siRNAs tested in planta (na - not specified): The percentage of asymptomatic plants 35 days after infection is given. For the bold-marked siRNAs and variants thereof (see Table 6), used in the form of esiRNAs / ERNAs or sRNAs derived therefrom oreASO (eNAs) against CMV, preferential patent protection is applied for in accordance with the claims. The respective SEQ ID NOs are indicated and listed separately as an "Addendum to Table 1." Figure 4. Efficacy of 21 nt and 22 nt esiRNAs / ERNAs against CMV RNA 2 in vitro and in planta. (A) Slicer assay (performed in a standardized and stringent manner as described in Figure 2) using examples of 21 nt esiRNAs / ERNAs and 22 nt variants derived from them. As shown, both variants have high slicing activity. AGO1 in particular, but also AGO2, exhibit slightly higher slicing activity in combination with 21 nt esiRNAs / ERNAs than with 22 nt esiRNAs / ERNAs. In contrast, the slicing activity of AGO2 in combination with 21 nt and 22 nt esiRNAs / ERNAs differs only minimally. Asterisks (*) mark the cleavage products generated by the slicing activity of AGO / RISC. (B) Comparison of the protective effect of 21 nt and 22 nt siRNAs.(Examples) In planta. Four- to five-week-old N. benthamiana plants were mechanically co-inoculated with 21 nt and 22 nt synthetic esiRNAs / ERNAs, respectively, as well as the genomic CMV RNAs. The percentage of asymptomatic plants is shown (dpi = days post inoculation). Both esiRNA / ERNA versions have a significant antiviral effect. (C) Representative plant images 28 days after mechanical co-inoculation. The percentage of asymptomatic plants per siRNA is indicated. Nine plants were used for the CMV-specific siRNAs and three plants for the siR gf698 control. All other controls were performed similarly to Figure 3. The numbers of the siRNA candidates correspond to the designations given previously and below in the figures, tables, and text (with abbreviations siR and siRCV, respectively). Figure 5. Slicer assay with esiRNAs / ERNAs identified against CMV RNA 3 (SEQ ID NO: 190). As described in theAs described in the application examples, "eNA screens" were performed with a double-stranded version of CMV RNA 3 (type Fny), and in the final step, slicer assays were performed with the resulting siRNA candidates (see also analogous description in Figure 2). AGO1 or AGO2 mRNA was translated in the presence of the siRNA to be tested in the BYL. The respective RISCs were thus programmed with the siRNA to be characterized, and the endonucleolytic hydrolysis of the radioactively labeled CMV target RNA 3 was detected by agarose gel electrophoresis and autoradiography. Asterisks (*) mark the cleavage products generated by slicer activity of the AGO / RISC. The standardized and stringently conducted slicer assay type served as the final definition of an esiRNA / ERNA: siRNAs are considered to be efficiently effective - and thus referred to as esiRNAs / ERNAs - if they induce the AGO / RISC-mediated hydrolysis of at least 25% of the original RNA in a slicer assay conducted in this way.induce the quantity of target RNA used in the respective assay (see also Table 2). (A) SiRNA candidates from the screen with AGO1. (B) SiRNA candidates from the screen with AGO2. All identified esiRNAs / ERNAs are summarized in Table 2. (C) Schematic representation of the binding sites of the most efficient esiRNAs / ERNAs on CMV RNA 3. Protein-coding regions are shown as gray boxes. The numbers of the siRNA candidates correspond to the designations given previously and below in the figures, tables, and text (with abbreviation siR or siRCV). As shown and described, a close correlation was observed between RNA cleavage activity in vitro and antiviral activity in vivo. Table 2. esiRNA / ERNA candidates against CMV RNA 3 (SEQ ID NO: 190). Listed below are three 21 nt long siRNAs identified from CMV RNA in the eRNA screens. The single-stranded guide and complementary passenger strands are listed. The siRNAs were designated as siRCV (CV forCMV) were named according to the respective target RNA (CMV-RNA3) and the position of the 5' end of the identified guide strand. The siRNAs were classified as described using standardized and stringent slicer assays: The percentage of the respective target RNA cleaved by the esiRNAs / ERNAs in the standardized and stringent slicer assays is given here. esiRNAs / ERNAs identified according to the definition (see above and Figure 2) are marked in bold: AGO1-selected black; AGO2-selected gray. Other siRNAs that were also identified in the screen but do not meet the definition of esiRNAs / ERNAs are shown in normal font. Some of the latter siRNAs (e.g., siRCV32061, 1132) served as negative controls for infection experiments in N. benthamiana. The efficiency in protection experiments with N. benthamiana is given for siRNAs tested in planta (na - not stated):the proportion of asymptomatic plants 35 days after infection. For the siRNAs marked in bold and variants thereof (see Table 6), used in the form of esiRNAs / ERNAs or sRNAs or eASOs derived therefrom (eNAs) against CMV, preferential patent protection is applied for in accordance with the claims. The respective SEQ ID NOs are indicated and listed separately as an "Addendum to Table 2." As shown and described, a correlation between RNA cleavage activity in vitro and antiviral activity in vivo was observed. However, this was not as pronounced as in the case of the esiRNAs / ERNAs identified against CMV RNA 2 (see also text). Figure 6. Characterization of the protective efficacy of esiRNAs / ERNAs in planta directed against CMV RNA 3. Four to five-week-old N. benthamiana plants were mechanically inoculated with the genomic CMV RNAs and individual synthetic esiRNAs / ERNAs (see Figure 3) and monitored for 28 days for the occurrence ofCMV-specific symptoms were checked (dpi = days post inoculation). (A) The graph shows the percentage of asymptomatic plants over the duration of the experiment. Traces with AGO1-specific esiRNAs / ERNAs are shown in black, with AGO2-specific esiRNAs / ERNAs and the siR gf698 control in gray. (B) The representative plant images illustrate the differences between asymptomatic and symptomatic plants 28 days after inoculation. The results are from three independent plant experiments. The percentage of asymptomatic plants and the number of plants used are indicated (n = 9–15). All other controls were performed similarly to that described in Figure 3. The numbers of the siRNA candidates correspond to the designations given previously and below in the figures, tables, and text (with abbreviations siR and siRCV, respectively). Figure 7. Comparison of the target sites of CMV(Fny)-specific esiRNAs / ERNAs in RNA 2 with thecorresponding potential target sites of these esiRNAs / ERNAs in the RNA 2 molecules of other CMV strains. (A) The scheme (“phylogenetic tree”) summarizes exemplary CMV strains and their membership in specific subgroups (II, IB, IA). The virus Fny from subgroup IA used for screening is marked with an arrow (modified from Roossinck, 1999). (B) The overviews show exemplary AGO1-specific (top) and AGO2-specific (bottom) esiRNAs / ERNAs from CMV RNA 2 and their sequence match with the target sites in the target RNAs of various CMV strains. The “expectation” value is a measure of the mismatches between the siRNA guide strand and the complementary target site. The higher the value, the lower the complementarity between the siRNA and the target site in the CMV RNA 2 of the respective CMV strain (https: / / www.zhaolab.org / psRNATarget / help#maxexpectation). Accordingly, the listed esiRNAs / ERNAs have a very high complementarity to thelisted genomic RNAs of the other CMV strains. Table 3. CMV(Fny)-specific esiRNAs / ERNAs that target RNAs 2 and 3 and have a complete match (complete agreement of the corresponding target sites) on RNAs 2 and 3 of other CMV strains. (A) The table lists esiRNAs / ERNAs (black from AGO1 screening; gray from AGO2 screening) that were identified from CMV(Fny) and whose target sites completely match potential target sites of selected CMV strains of subgroup IA (see also Figure 7). The numbers correspond to the respective siR or siRCV in the previous figures and tables. (B) The table lists esiRNAs / ERNAs (labeled as above) identified from CMV(Fny) whose target sites fully match potential target sites of selected CMV strains of subgroup IB. The esiRNAs / ERNAs identified from CMV(Fny) did not fully match potentialTarget sites in RNAs 2 and 3 of selected CMV subgroup II strains (see Table 6). The numbers of the siRNA candidates correspond to the designations given above and below in the figures, tables, and text (with abbreviations siR and siRCV, respectively). The information is analogous for other sRNAs and eASOs whose sequence is derived from these esiRNAs / ERNAs. Table 4. Protective potential against CMV 2 RNAs. The esiRNAs / ERNAs marked with a (+) have completely complementary target sites in the genomic RNA molecules of selected CMV strains. According to the data obtained with strain Fny, particularly broad protection against CMV infection can be achieved by using the esiRNAs / ERNAs identified from CMV RNA 2, which are highlighted in grey and marked with a (+), since these have completely complementary target sites in five to six of the CMV strains selected for comparison. Thus, a combination of different esiRNAs / ERNAs can be used against allThe CMV strains of subgroups IA and IB considered here (and probably other representatives of these subgroups) can be protected in protection experiments. By appropriate variation of the esiRNAs / ERNAs, i.e., exchange of one or more indexed nucleotides (see Table 6), the identified esiRNAs / ERNAs can also be used against strains of subgroup II. The information is analogous for other sRNAs and eASOs whose sequence is derived from these esiRNAs / ERNAs. Table 5. Protective potential against CMV 3 RNAs. The siRNAs marked with a (+) have completely complementary target sites in the selected CMV strains. A particularly broad protection against CMV infection can be achieved by using the esiRNAs / ERNAs identified from CMV RNA 3, which are highlighted in grey and marked with a (+), since these have completely complementary target sites in five to six of the CMV strains selected for comparison.A combination of different esiRNAs / ERNAs can thus be used to protect against all CMV strains of subgroups IA and IB (and other representatives of these subgroups) considered here in protection experiments. By appropriately varying the esiRNAs / ERNAs, i.e., exchanging one or more indexed nucleotides (see Table 6), the identified esiRNAs / ERNAs can also be used against strains of subgroup II. The information is analogous for other sRNAs and eASOs whose sequence is derived from these esiRNAs / ERNAs. Table 6. Correspondence of the target sites of CMV(Fny)-specific esiRNAs / ERNAs with potential target sites of these esiRNAs / ERNAs in the genomic RNAs of other CMV strains. (A) The table shows esiRNAs / ERNAs (the numbers correspond to the respective siR or siRCV in the previous figures and tables) that were identified from CMV(Fny) and whose target sites partially overlap with potential target sites of selected CMV strains of subgroup IAmatch. The number of respective mismatches is indicated in parentheses. (B) The table shows esiRNAs / ERNAs identified from CMV(Fny) whose target sites partially match potential target sites of selected CMV strains of subgroups IB and II. The specificity of binding of an sRNA to the target site of a target RNA is ensured for mismatches of up to 5, but at higher melting temperatures of the complementary RNA strands, often even with a number of mismatches that is at least 2 nucleotides higher (Liu et al., 2014). As shown in Table 6, with the exception of 4 strains in which the number of mismatches is higher, the identified esiRNAs / ERNAs, even with a number of 7 mismatches to the target site, provide potential protection in RNA silencing procedures for all other strains. On this basis, the claimed scope of protection (see below) for eNAs that have changes in 1-7 positions is justified.Candidate numbers correspond to the designations given above and below in the figures, tables, and text (abbreviated as siR or siRCV). The information is analogous for other sRNAs and eASOs whose sequence is derived from these esiRNAs / eRNAs. Figure 8: Schematic representation of the organizational forms of edsRNAs. edsRNAs are generated either by hybridization of two separate complementary RNA molecules (a) or by hybridization of complementary regions of an RNA molecule (b). In case of (b), the RNA molecule contains a spacer (see text for definition). This spacer can be reduced in size or completely removed (processed) by various mechanisms (e.g., splicing or endonuclease activities), which can lead to other forms of RNA hairpin molecules or similarly structured dsRNAs as in case (a). edsRNAs, as in (a), are obtained in the simplest case by hybridization of independently produced complementary RNA molecules(see also application examples and Figures 9 and 10). Black and gray boxes: pseudo (p)-siRNAs (see text for definition) with variable sequences at the 5' and 3' ends, respectively; (s) sense, (as) antisense. A, B…Y…Z represent 1 to n (or in reverse order n-1) esiRNA / ERNA sequences identified from a screen with an AGO protein (A) or other AGO proteins (B…, Y, Z) and incorporated into the edsRNA sequence; (s) sense, (as) antisense. R: Hammerhead or hepatitis delta virus (HDV) ribozyme. The ribozymes were used to generate the transcript ends via self-splicing. They are no longer functional after the respective edsRNA has been generated. Examples of edsRNAs constructed according to a) are given in Figures 9 and 10. Examples of the composition of cDNA constructs with which edsRNAs designed according to a) and / or b) can be generated are given in Figure 11. Figure 9. Exemplary edsRNA and control dsRNAs. Shown is theStructure of an edsRNA generated from two transcripts according to the scheme in Figure 8 A). The edsRNA contains 21 nt long esiRNA / ERNA sequences, which have been shown to be effective against CMV RNA 2 in the RNA silencing / RNAi process and to be antivirally protective in planta (numbering according to Figure 2 and Table 1). In addition, two dsRNAs are shown, which are classically constructed, i.e., not from esiRNA / ERNA sequences, but from uninterrupted (continuous) regions of the target RNAs, and were used as controls. (A) Exemplary edsRNA 'dsCMV6si21'. This consists of a 21 nt pseudo-siRNA at each end (symbolized by asterisks (*)) and six 21 nt sequences of esiRNAs / ERNAs directed against CMV RNA 2, which are active in plant AGO1 / RISCs or AGO2 / RISCs. Guide strands (gs) are shown as arrows pointing in the sense direction 5'-3'. The AGO1-specific gs are located on one end, theAGO2-specific gs on the other RNA strand. The example RNA shown here is blunt, meaning there are no protruding nucleotides at the ends. However, edsRNAs with protruding ends (Ü) were also generated and tested (see below). Regarding their protective efficiency, the results obtained were identical with both forms of edsRNAs. The protective efficiency was also analogous with edsRNAs generated from a transcript according to the scheme in Figure 8 B) or Figure 11 (not shown). (B) Control dsRNA 1. The dsCMV also consists of pseudo-siRNA sequences at the ends as well as a double-stranded 126 nt long section (corresponding to a length of six 21 nt long siRNAs) of CMV RNA 2 and the complementary sequence corresponding to the section of CMV RNA 2. Important: The dsCMV also coincidentally contains the sequences of two siRNAs that were identified as esiRNAs / ERNAs in the eNA screen against CMV RNA 2 (see Figure 10). (C) Control dsRNA 2.The dsGFP also consists of pseudo-siRNA sequences at the ends and a 126 nt long double-stranded region consisting of the GFP mRNA (mRNA encoding the green fluorescent protein) and the complementary sequence corresponding to this region of the GFP mRNA. The exact sequences of the dsRNAs shown are shown in Figure 10. Figure 10. Structure / sequences of exemplary edsRNAs and the control dsRNAs used (schematically shown in Figure 9). Shown are the sequences of two edsRNAs, dsCMV6si21 and dsCMV6si22, which are composed of pseudo-siRNA sequences (at the termini) and esiRNA / ERNA sequences, as well as the control dsRNAs shown in Figure 9, dsCMV and dsGFP, which are composed of pseudo-siRNA sequences at the termini and otherwise continuous regions of the CMV RNA 2 and GFP mRNA, respectively (the sense and antisense strands are shown in each case). The edsRNAs contain 21 nt or 22 nt long esiRNA / ERNA sequences, which have been shown to bind to CMV RNA 2 in the RNA.silencing / RNAi process and are antivirally protective in planta (Figures 2-4). dsCMV6si21 consists of a 21 nt pseudo-siRNA at each end and six 21 nt CMV-specific esiRNAs / eRNAs (three each active in AGO1 / RISC and AGO2 / RISC). The AGO1-specific guide strands (gs) are located on one RNA strand, and the AGO2-specific gs on the other. Since the gs of an siRNA on the dsRNA overlaps with the 2 nt 3' overhang of the passenger strand of the subsequent siRNA, partial modifications were made to the two 3'-terminal nucleotides of the passenger strands at these sites to ensure complete complementarity of the edsRNA. The dsCMV6si22 is constructed according to the same principle and consists of a 22 nt pseudo-siRNA at each end and six 22 nt CMV-specific esiRNAs / ERNAs (three each active in AGO1 / RISC and AGO2 / RISC). The AGO1-specific gs are located on one end, the AGO2-specificgs on the other RNA strand. The different RNA segments are marked as follows: dsCMV6si21 and 22 (5'-3'): bold black pseudo-siRNA, dark gray siRCV21, 172 gs, light gray siRCV2, 1489 gs, italic black siRCV2, 359 gs. gs – guide strand dsCMV6si21 or 22 (3'-5'): bold black-pseudo-siRNA, light gray-siRCV2380 gs, italic black-siRCV2 2041 gs, dark gray-siRCV21020 gs The dsCMV also consists of pseudo-siRNA sequences at the ends as well as a 126 nt long double-stranded section (corresponding to a length of six 21 nt long siRNAs) from the CMV RNA 2. Important: The section selected from the CMV RNA 2 randomly contained two siRNAs that were identified in the eNA screen (see above) as esiRNAs / ERNAs (siRCV2557 and siRCV2 540: underlined and italic respectively). The dsGFP also consists of pseudo-siRNA sequences at the ends and a 126 nt long double-stranded portion of the GFP mRNA. This dsRNA contains the sequence of theExperiments used control siRNA siR gf698 (lowercase letters). The respective SEQ ID NOs are indicated. Figure 11. Exemplary structure of cDNA constructs / templates with which edsRNAs with different structures can be generated in vitro or in vivo in various ways. The cDNAs shown contain different, exemplary promoters (phage T7 RNA polymerase, Pol II, and Pol I promoters (Pol II and Pol I promoters, for example, from Saccharomyces cerevisiae)) via which edsRNAs can be transcribed from these cDNAs. The generated edsRNAs contain at least one pseudo-siRNA sequence and esiRNA sequences, which here correspond to the esiRNA sequences identified as directed against CMV (identical to the esiRNA / eRNA sequences in the edsRNA constructs shown in Figures 9 and 10). As mentioned, the esiRNA sequences used are exemplary, ie in other, otherwise analogously constructed cDNA constructs, completelydifferent pseudo-siRNA sequences or esiRNA / ERNA sequences may be included (see Figure 8 and text). In addition to the complementary pseudo-siRNA or esiRNA sequences, the cDNAs also encode a spacer sequence, which here, again as an example, encodes a cellular intron (actin 1) and can be spliced ​​by the cellular splicing machinery or degraded by cellular RNAases. In addition, the cDNAs encode ribozymes (HH ribozyme or HDV ribozyme), which, after transcription, generate one or both termini of the edsRNA by self-splicing. Furthermore, they encode transcription terminators (here, for example, VSV or cellular Pol terminators) and restriction sites for cloning purposes. The respective sequences, which may in some cases overlap (see text above), are marked in different ways. The respective SEQ ID NOs are indicated. edsRNAs are generated via T7 RNA polymerase construct 1.1. edsRNA is expressed as a hairpin transcriptgenerated. Construct contains: promoter of the T7 RNA polymerase (T7 promoter); esiRNA sequences and a pseudo-siRNA sequence located unilaterally terminal to the esiRNA sequences; the actin-1 intron as a spacer, the hepatitis D virus (HDV) ribozyme; the vesicular stomatitis virus (VSV) transcription terminator; and restriction sites (Spe I / Xba I) for cloning. Construct 1.2. edsRNA is generated as a hairpin transcript, which is further processed. Construct contains: T7 promoter; esiRNA sequences and two pseudo-siRNA sequences located bilaterally terminal to the esiRNA sequences; the actin-1 intron as a spacer; the HDV ribozyme; the VSV transcription terminator; and restriction sites (Spe I / Xba I) for cloning. edsRNAs generated via RNA polymerase II (Pol II) construct 2. edsRNA is generated as a hairpin transcript, which is further processed. cDNA is cloned behind a cellular Pol II promoter, which is potentially inducible (e.g., Gal1 promoter ofSaccharomyces cerevisiae) and termination occurs via a 3'-sided Pol II terminator (e.g. CYC1 terminator from Saccharomyces cerevisiae). Construct contains: Hammerhead ribozyme (HH ribozyme); esiRNA sequences as well as a pseudo-siRNA sequence that is located unilaterally terminal to the esiRNA sequences; the actin-1 intron as a spacer; the hepatitis D virus (HDV) ribozyme; restriction sites (Hind III / Xba I) for cloning. edsRNAs generated via RNA polymerase I (Pol I) construct 3.1. edsRNA is generated as a hairpin transcript. Construct contains: A cellular Pol I promoter; esiRNA sequences as well as a pseudo-siRNA sequence that is located unilaterally terminal to the esiRNA sequences; the actin-1 intron as a spacer; the hepatitis D virus (HDV) ribozyme; a minimal Pol I terminator; restriction sites (SpeI / XbaI) for cloning. Construct 3.2. edsRNA is generated as a hairpin transcript, which is further processed. Construct contains: Pol I promoter;esiRNA sequences and two pseudo-siRNA sequences located 5' and 3' of the esiRNA sequences; the actin-1 intron as a spacer; the HDV ribozyme; the Pol I terminator; and restriction sites (Spe I / Xba I) for cloning. Figure 12. Processing of an edsRNA by DCLs in vitro. Radioactively labeled dsCMV6si21 was added to BYL, and processing by DCL4, DCL2, and DCL3, which are endogenously present in the extract, was monitored over a period of 24 h. Samples taken from the BYL at the indicated time points after addition of the dsRNA were separated by PAGE and visualized by autoradiography (M = 21 nt siRNA as a marker). The defined banding pattern suggests defined processing of the edsRNA by the DCL proteins. This results in a significant proportion of 21 nt siRNAs. Figure 13. Slicer assay with individual AGO1- and AGO2-specific esiRNAs / ERNAs from CMV RNA 2 as well as with the analogous esiRNAs / ERNAs derived from an edsRNA in BYL.generated. In BYL, AGO1 or AGO2 / RISC were reconstituted with individual esiRNAs / ERNAs, with a corresponding mix of these esiRNAs / ERNAs, or esiRNAs / ERNAs that were processed in BYL from the edsRNA 'dsCMV6si21' by the DCL present there. Endonucleolytic hydrolysis of the radiolabeled target RNA was detected by agarose gel electrophoresis and autoradiography. Asterisks (*) mark the cleavage products generated by the slicing activity of AGO / RISC. Both the individual siRNAs and the siRNAs processed from the edsRNA lead to the efficient cleavage of the target RNA into the expected cleavage products. Figure 14. NGS RNA-seq analysis of siRNAs generated in BYL from an edsRNA (containing the sequences of 21 nt esiRNAs / ERNAs). The proportions of reads from 21 nt esiRNAs / ERNAs to the total of all 21 nt reads are shown. (A) Proportion of esiRNA / ERNA guide and passenger strand reads based on their position on theedsRNA dsCMV6si21 used. (B) Proportion of guide and passenger strand reads per esiRNA / ERNA. All CMV-specific esiRNAs / ERNAs could be detected. This shows that they are processed from the corresponding edsRNA by DCL4 contained in BYL. (C) Comparison of the percentage of detectable guide and passenger strands of CMV-specific siRNAs generated from the edsRNA. It is clear that the esiRNAs / ERNAs used are found in a high proportion (approximately 60% of the reads) and are thus preferentially generated from the edsRNA by DCL4. Figure 15. Comparison of the protective effect of various dsRNAs in planta. Four- to five-week-old N. benthamiana plants were mechanically inoculated with various dsRNAs or single-stranded components of certain dsRNAs. At the same time, the genomic, infectious CMV RNAs were administered (co-inoculated), which, in the absence of mediated protection, trigger infection.is the percentage of asymptomatic N. benthamiana plants over a period of 35 days (dpi = days post inoculation). (A) Percentage of asymptomatic plants after administration of dsCMV62i21-Ü, dsCMV6si22-Ü, dsCMV, and dsGFP. (B) Representative plant images for the experiment shown in (A). The use of dsCMV6si21-Ü, consisting of six 21 nt CMV-specific esiRNAs / ERNAs, confers very efficient (100%) protection against CMV infection. With the analogous construct, consisting of 22 nt variants of the same esiRNAs / ERNAs, a reduced protection (30%) of the plants against CMV infection was achieved. The conventionally constructed dsCMV (containing two esiRNA / ERNA sequences) provides significantly reduced protection, while dsGFP provides no protection. (C) Comparison of the protective effect of dsRNAs and single-stranded RNAs, which correspond to the constituent single strands of the dsRNAs (see text).Application example). As shown, only the double-stranded RNA consisting of several CMV-specific esiRNAs / ERNAs (dsCMV6si21-Ü) provides very effective protection against CMV infection. The conventionally constructed dsCMV and all single-stranded components of the dsRNAs, in contrast, do not provide any protection. This suggests that the protection against viral infection mediated by the edsRNA is based on its processing into esiRNAs / ERNAs by plant DCLs (see text Application examples). Table 7. Sequences and activities of the esiRNAs / ERNAs identified in the respective screens against three different mRNA targets against M. incognita. The siRNAs, listed again as single-stranded guide and complementary passenger strands, were identified via “eNA screens” as described in the application examples and classified as esiRNAs / ERNAs via slicer assays: The percentage of the esiRNAs / ERNAsThe cleaved quantity of the respective target RNA in the standardized and stringently conducted slicer assays. As indicated by the marking (bold), all listed siRNAs met the corresponding criterion of at least 25% cleavage efficiency of the originally used target RNA. The siRNAs were named siRMI (MI for M. incognita) according to the respective target RNA (SPF - Splicing factor SEQ ID NO: 191; INT - Integrase SEQ ID NO: 192; ACT - Actin 4 SEQ ID NO: 193) and the position of the 5' end of the identified guide strand. It is also indicated whether the esiRNAs / ERNAs have a nematicidal effect in planta (yes / nt - not yet tested). Finally, the activity of the esiRNAs / ERNAs after soaking in vivo is also shown: The normalized expression rate (NER) of the respective mRNAs, determined by qRT-PCR (see also Figure 14), is given (determined via qRT-PCR). The values ​​(in percent) indicate the proportion of cleavedProduct again: For example, in the case of siRMISPF 441, 90% of the mRNA is sliced ​​in vivo after treatment (compared to 0% after treatment with siR gf698). As shown and described, a close correlation between RNA cleavage activity in vitro and in vivo was observed. Listed are those RNAs and variants thereof, according to the claims and used against M. incognita in the form of esiRNAs / ERNAs or sRNAs or eASOs derived therefrom (eNAs), for which patent protection is applied for. The respective SEQ ID NOs are indicated and listed separately as an "Addendum to Table 7". Figure 16. Silencing of the splicing factor mRNA of M. incognita by identified esiRNAs / ERNAs in vivo and in planta. A) In vivo: Normalized expression rate (NER) of splicing factor mRNA (SPF SEQ ID NO: 191) determined by qRT-PCR (shown is the still measurable quantity of mRNA) after incubation of J2-stage nematode larvae (J2s) for 24 hours in siRNA solution (siRMISPF 166, siRMISPF220 and siRMISPF 441). For gene-specific reverse transcription (RevertAid Reverse Transcriptase) to cDNA according to a standard procedure, approximately 500 ng of total RNA or 1 / 5 diluted cDNA was used as PCR template. MI 18S rRNA (HE667742) was used as the reference gene in the quantitative RT-PCR. The normalized expression rates (NER) were calculated using the mathematical method 2. -ddCtusing the mean Ct value of the reference gene. Two representative experiments with two replicates each are shown (water – water control without siRNA; siR GFP (or siR gf698) – negative control: measured mRNA quantity 100%). B) In planta / number of eggs (eggs-J2 s) in tomato roots. J2s were incubated in water for 24 hours in the presence of control siRNA (siR GFP or siR gf698) or test siRNA. The ability of the nematodes to establish infection in roots of tomato plants (two-week-old, n=15) and complete their life cycle was analyzed by counting eggs (eggs J2) 56 days post-infection. Error bars: standard deviation of the mean (SDM). Asterisks indicate statistical differences from controls at p≤ 0.05 (*), p≤ 0.01 (**), and p≤ 0.001 (***), determined using a two-tailed Student's t-test. A representative experiment is shown. Figure 17. Silencing of actin 4 and integrase mRNAs in vivo.The representative experiments shown here were performed analogously to Figure 17. A: Normalized expression rate (NER) of actin 4 mRNA (ACT SEQ ID NO: 193) determined by qRT-PCR (see Figure 15) after 24 h incubation of J2 stage nematode larvae (J2s) in siRNA solutions (siR 154, siR 200, siR 303, siR 419, siR 433, siR 435 and siR 661). B: Normalized expression rate (NER) of integrase mRNA (INT SEQ ID NO: 192) determined by qRT-PCR (see Figure 15) after 24 h incubation of J2-stage nematode larvae (J2s) in siRNA solutions (siR 135, siR 273, siR 423, and siR 444). Error bars: standard deviation of the mean (SDM). Asterisks indicate statistical differences from controls at p≤ 0.05 (*), p≤ 0.01 (**), and p≤ 0.001 (***), determined using a two-tailed Student's t-test. Table 8. Sequences of the esiRNAs / ERNAs against B. cinerea identified in the respective screens against various mRNA targets.The siRNAs, listed as single-stranded guide and complementary passenger strands, were identified using "eNA screens" as described in the application examples and classified as esiRNAs / ERNAs using slicer assays: The percentage of the quantity of the respective target RNA cleaved by the esiRNAs / ERNAs in the standardized and stringently performed slicer assays is given here. The siRNAs were named siRBC (BC for B. cinerea) according to the respective target RNA (VDS - VDS51 SEQ ID NO: 194; DCTN - DCTN1 SEQ ID NO: 195; SAC - Sac1 SEQ ID NO: 196; ERG - ERG27 SEQ ID NO: 197; EF - EF2 SEQ ID NO: 198; CHS - CHS1 SEQ ID NO: 199) and the position of the 5' end of the identified guide strand. esiRNAs / ERNAs are marked in bold: For these bold-marked siRNAs and variants thereof (see Table 6), used in the form of esiRNAs / ERNAs or derived sRNAs or eASOs (eNAs) against B.cinerea, preferential patent protection is applied for in accordance with the claims. The respective SEQ ID NOs are indicated and listed separately as an "Addendum to Table 8". Figure 18. Slicer assays with esiRNAs / eRNAs identified against various B. cinerea mRNAs. The siRNAs were identified using "eNA screens" as described in the application examples and classified using standardized and stringent slicer assays. The slicer assays were carried out as described above with AGO1 from Colletotrichum graminicula (see text). The translation reaction of C. graminicula AGO1 was carried out in the presence of the synthetic siRNA duplexes to be tested, resulting in the incorporation of the desired siRNAs into the AGO / RISC. The radiolabeled mRNAs were then added as target RNA. Total RNA was isolated from the mixtures and analyzed for cleavage products using denaturing PAGE and autoradiography.The target RNAs used (VDS stands for VDS51; DCTN for DCTN1; SAC for Sac1; ERG for ERG27; EF for EF2) and the resulting cleavage products are labeled. The siRNAs are named according to Table 8. For comparison, siRNAs (257, 470, 653, 808) were used in the assay, which were determined by in silico prediction (https: / / www.zhaolab.org / pssRNAit / ). As a control, the slicer assay was performed without siRNA (-). As a further control, originally used dsRNAs (ds) or pools of siRNAs (“pool”) were applied to the gel. Figure 19. Inhibition of B. cinerea growth by topical application of esiRNAs / ERNAs directed against defined target RNAs. (A) Bar graphs depicting the size of lesions developed by B. cinerea on leaves of Arabidopsis thaliana (wild-type form; Col-0). The plants were treated with suspensions of B.cinerea spores and various combinations of siRNAs were inoculated: i) a mixture of six esiRNAs / ERNAs targeting Erg27 mRNA (siRBCERG); ii) a mixture of four esiRNAs / ERNAs targeting Erg27 mRNA, two esiRNAs / ERNAs targeting SacI mRNA, and one esiRNA / ERNA targeting Ef2 mRNA (siRBCMIX); and iii) one siRNA targeting GFP mRNA (siR gf698 and siR GFP, respectively). Twelve plants were used for each treatment, and three leaves (leaves 8, 9, and 10) were inoculated per plant. A drop of the suspensions containing the spores and 400 ng (siR gf698 or siR GFP), 2400 ng (siRBCERG), or 2800 ng (siRBCMIX or siR GFP) of RNAs was placed on each leaf. Suspensions without RNAs ("water") were used as a fungal growth control.The lesion area on the leaves (see examples lower panel) was determined 3 days after inoculation (dpi) using ImageJ software, and the sizes were divided into five categories: i) >50 mm. 2 (+++), ii) 20-50 mm 2 (++), iii) 10-20 mm 2 (+), iv) 1-10 mm 2 (+ / -), and v) 0 mm 2(-). The different categories are indicated as percentages. Representative images of leaves with lesions of the different categories (lower panel). (B) qRT-PCR determination of Erg27 mRNA levels in vivo (during the fungal infection process). Total RNA was extracted from the fungal lesions on the leaves at 3 dpi, and cDNA was generated using a standard protocol. For subsequent PCR amplification, two primer sets were used that cover the regions targeted by the various esiRNA / ERNAs (upper panel). The Erg27 mRNA level was normalized to the endogenous level of B. cinerea actin mRNA (“housekeeping”). The normalized expression rate (NER) is indicated; see also previous figures. The bars represent the mean of four biological replicates (each containing six lesions from independent leaves), the error bars, and the SDM (standard deviation of the mean; lower panel).Statistically significant differences from the water control ("Water") were determined using a two-sided Student's t-test: *p≤0.05, *p≤0.01, ***p≤0.001. Application examples Application example 1: Nucleic acid agents against Cucumber mosaic virus, CMV The described "eNA-screen" method was applied for the first time in this form to two RNA segments of the CMV genome (strain Fny) as target RNAs: RNA 2 (SEQ ID NO: 189) encodes the 2a protein and the subgenomic RNA 4A, which in turn encodes the viral suppressor of RNA silencing (VSR), 2b. RNA 3 (SEQ ID NO: 190) encodes the 3a protein and the subgenomic RNA 4, which in turn encodes the capsid protein (CP) (Figure 2D and Figure 5). The screening was performed with both AGO1 (L version; Gursinsky et al., 2015) and AGO2 from Nicotiana benthamiana (Nb). The target RNAs were used in double-stranded form in the screens.Against CMV RNA 2, a series of siRNAs, NbAGO1L and NbAGO2, were identified and classified as esiRNAs / ERNAs (Figure 2; Table 1). As described above, the classification as esiRNAs / ERNAs was carried out in the final step of the “eNA screen” in standardized and stringently performed slicer assays (protocol modified from WO 2019 / 001602; WO 2022 / 200407 and Gago-Zachert et al., 2019; see also general description of the procedure above): To form the RISC, 0.5 pmol of the mRNA of the AGO protein to be used was translated in a reaction solution (Gago-Zachert et al., 2019) containing 50% (v / v) BYL with defined protein quantity and translation activity in the presence of 10-100 nM of the synthetic siRNA to be characterized and a 10-fold excess (0.1-1 µM) of a competitor siRNA (siR gf698).The quantity of siRNA used to be tested was adjusted to the activity of the respective AGO protein with the siRNA siR gf698 on its GFP mRNA target. SiR gf698 meets the criteria of an esiRNA / ERNA on the GFP mRNA (Schuck et al., 2013). After an incubation period of 2.5 h at 25 °C, 3.4 pmol of a nonspecific mRNA (encoding the firefly luciferase protein) were added to each reaction as additional competitor RNA and 10 fmol of the radioactively labeled target RNA, and the reaction mixtures were incubated again for 15 min at 25 °C. During this incubation, the target RNA is cleaved by the formed AGO / RISC, if necessary. The further conditions and the analysis of the cleavage reaction corresponded to Gago-Zachert et al., 2019: After gel electrophoresis of the extracted RNA, the remaining quantity of target RNA was quantified compared to a control reaction (performed without siRNA).of the resulting cleavage products by measuring the bathing intensities (ImageQuantTL or ImageJ). Classification as esiRNA / ERNAs was based on the measured cleavage activity (slicer activity) of the RISC formed with this siRNA on the target RNA (see also tables): If at least 25% of the quantity of target RNA originally used in the assay was endonucleolytically converted to cleavage products under standardized and stringent (competitive) conditions, this siRNA was designated as effective, i.e., esiRNA / ERNA. The 25% cleavage efficiency threshold was determined based on previous data (Gago-Zachert et al., 2019) and the data obtained here, which show that esiRNAs / ERNAs that exhibit this characteristic in vitro have a clearly measurable antipathogenic effect in vivo compared to control siRNAs (see below). On this basis, esiRNAs / ERNAs were characterized that are particularly active in cleaving AGO1 on CMV RNA 2.These included, for example, siRCV2359, siRCV21172, and siRCV21489 (the candidates are named with "siR," "CV" for CMV, the respective RNA, and the position of the viral (+)RNA to which the 5' nucleotide of the siRNA guide strand is complementary). SiRCV2149, siRCV2186, siRCV21613, siRCV21982, siRCV22441, siRCV22562, and siRCV22727 also exhibited high cleavage activity. The functional in vitro data with these siRNAs are shown in Figure 2; the sequences of these siRNAs are summarized in Table 1 (in the Supplement to Table 1 with the respective SEQ ID Nos.). Similarly, siRCV2 380, siRCV2 1020, and siRCV2 2041 were identified as particularly cleavage-active RNA agents in the RISC complex together with AGO2. SiRCV2407, siRCV2449, siRCV2540, siRCV2557, siRCV21054, and siRCV21248 also exhibited a high cleavage rate (Figure 2; Table 1). The binding sites of the particularly cleavage-active (most efficient) siRNAs located on RNA 2 are shown schematically in Figure 2C.As examples, the in vitro identified esiRNAs / ERNAs siRCV21020, 1172, 359, 1489, 380 and 2041 were used in protection experiments in planta. For this purpose, a statistically representative number of N. benthamiana plants (n=12-15) were co-inoculated with Carborundum using a standard protocol (“rub-in”) with 150 pmol (~1 µg) of the siRNA to be tested (synthetically obtained from a company) and 20 fmol each of the genomic CMV RNAs (1-3; produced by in vitro transcription starting from “infectious cDNAs” (obtained from Prof. Fernando García-Arenal Rodríguez (Polytechnic University of Madrid) and Prof. John Carr (University of Cambridge); Rizzo and Palukaitis 1990) per plant (RNAs dissolved in 15 mM KH2PO4, 25 mM glycine solution). The infection with the CMV RNAs was carried out in such a way that the respective quantity of RNAs, when inoculated into N. benthamiana without additives, resulted in 100% leads to an infection with significant symptom development (so-called “maximum challenge”).The nonspecific siR gf698 and siRNAs that showed no or only minimal cleavage activity on the target RNA in the previously conducted screen (siRCV21844 and siRCV22634) were used as controls. The plants were examined for symptom development over 35 days (dpi; days post infection). Figure 3 A shows representative images of plants treated in this manner, while Figure 3 B shows the overall progression across multiple experiments (three biological replicates). It became clear that 93% protection against CMV infection can be achieved with siRCV2 359 and siRCV21489, and 100% protection against CMV infection can be achieved with siRCV21020 and siRCV21172. This means that all, or the clear majority, of the plants treated in this way remained symptom-free at the maximum challenge applied. With siRCV2380 and siRCV2 2041, 60% protection against CMV infection was achieved, meaning that 40% of these plants developed symptoms upon challenge.The various negative control siRNAs provided little or no protection: only 0–7% of the treated plants remained asymptomatic during the challenge. This protective effect was also confirmed by the fact that in plants that were identified as asymptomatic by eye after 35 dpi after treatment with the respective protective esiRNAs / ERNAs, genomic CMV RNA was no longer detectable by RT-PCR (standard procedure) (Figure 3 C). Plant protection against CMV infection was also achieved with 22 nt versions of the respective esiRNAs / ERNAs. This is shown exemplarily in Figure 4: 22 nt esiRNA / ERNA versions showed similar, in some cases slightly lower, slicer activity in the respective AGO / RISC on the target RNA in in vitro slicer assays.A similar trend was observed in plant protection experiments: Protection with 22 nt siRNAs was either comparably good or slightly reduced compared to the situation with 21 nt esiRNAs / ERNAs (shown as examples in Figure 4 with siRCV2359 and siRCV21020). Slicer assays and protection experiments with 24 nt versions of the respective esiRNAs / ERNAs showed similar results to the experiments conducted with the 22 nt esiRNAs / ERNAs (not shown). Using the same procedure, three esiRNAs / ERNAs were identified against CMV RNA; again, NbAGO1L and NbAGO2 were used. Here again, a number of siRNAs were identified that showed very high (siRCV3239, siRCV3507, siRCV3985) and high (siRCV3 151, siRCV3988, siRCV31098) binding to AGO1 and very high (siRCV3593, siRCV31019, siRCV31569) and low binding to AGO2.induce a high (siRCV3358, siRCV3478, siRCV3496, siRCV3592, siRCV3733, siRCV31394) slicer activity against the CMV target RNA 3 (Figure 5 A, B). The positioning of the most efficient siRNA guide strands on RNA 3 in the slicer assay is shown in Figure 5 C. Table 2 summarizes the results from the screen of esiRNAs / ERNAs (in the supplement to Table 2 with the respective SEQ ID NO) against CMV RNA 3. In comparison, the esiRNAs / ERNAs characterized against CMV RNA 2 showed a tendency towards higher slicer activity than the esiRNAs / ERNAs identified against RNA 3 (see Tables 1 and 2). The reasons for this could be a slightly higher stability or fundamentally more compact structure of CMV RNA 3 (less accessibility of a-sites) compared to CMV RNA 2 (data not shown). In protection experiments in plants, the 21 nt and 22 nt esiRNAs / ERNAs characterized against CMV RNA 3 showed effective protection against the virus.As expected from the in vitro experiments, this was somewhat lower than was the case with the esiRNA / ERNA active substances against CMV RNA 2 (Figure 6). Slicer assays and protection experiments with 24 nt versions of the respective esiRNAs / ERNAs showed similar results to the experiments conducted with the 22 nt esiRNAs / ERNAs (not shown). Sequence comparisons revealed that many of the esiRNAs / ERNAs identified here from the CMV strain Fny are also effective on the analogous RNA segments of other CMV strains, because there is complete complementarity between the sequences of the respective guide strands of these esiRNAs / ERNAs and the respective target sites on the viral RNAs. Figure 7 shows the sequence correspondences to the complementary target sites on the RNA 2 genome segments of CMV for six esiRNAs / ERNAs (modified from Roossinck, 1999).Furthermore, the figure shows calculated expectation rates for RNA-RNA mismatches (missing base pairing at one or more positions in the nucleic acid when the siRNA guide strand binds to the target site). Based on these data, Table 3 provides a complete overview of the identified esiRNAs / ERNAs whose guide strands bind completely complementarily, i.e. without mismatches, to the target sites in RNAs 2 and 3 of the respective CMV strains. As can be seen from the table, these esiRNAs / ERNAs are therefore protective against virtually all CMV strains of groups IA and IB, either when used individually or in combination. This is illustrated in Tables 4 and 5. As can be seen from Tables 3 - 5, none of the identified esiRNAs / ERNAs binds without a mismatch to the corresponding target sites in RNAs 2 and 3 of the CMV strains of subgroup II.As explained above and previously described in an application (WO 2022 / 200407), esiRNAs / ERNAs indicate so-called a-sites, i.e., regions containing the target sites of these esiRNAs / ERNAs in complexly structured target RNAs, which, despite their structuring, are accessible to RISC or other endonuclease-containing cellular complexes (WO 2022 / 200407). Accordingly, silencing of genomic RNAs 2 and 3 of subgroup II strains can still occur by adapting the sequences of the esiRNAs / ERNAs identified here to the target sites in the target RNAs, i.e., by avoiding mismatches. This is summarized in Table 6: The number of mismatches of the guide strands of the identified esiRNAs / ERNAs upon binding to the respective target sites in RNAs 2 and 3 of the various CMV strain subgroups is shown here. The table shows all types of mismatches. These can include both the so-calledThe seed region of the siRNAs, the most important interaction region of an siRNA with the target RNA during the AGO / RISC-mediated silencing process (Jackson and Linsley, 2010), as well as the 5' end of the RNA, which has been shown not to be involved in siRNA binding. The specificity of binding of an sRNA to the target site of a target RNA is ensured for mismatches of up to 5, but at higher melting temperatures of the complementary RNA strands, often even with a number of mismatches that is at least 2 nucleotides higher (Liu et al., 2014). As shown in Table 6, with the exception of four strains in which the number of mismatches is higher, the identified esiRNAs / eRNAs, even with a number of 7 mismatches to the target site, provide potential protection in RNA silencing procedures for all other strains.Summarizing these data, the population of esiRNAs / ERNAs identified here can be used for protection purposes against most CMV strains, either in their unmodified form (as with most members of the 1a and 1b subgroups) or varied at 1 to a maximum of 7 nucleotides (Table 6). As the table shows, according to the invention, the mapped esiRNAs / ERNAs, even with a variation range at 7 positions, can target virtually 95% of all compared CMV strains. In the same context, it is important to note that the esiRNAs / ERNAs can be used either individually or, even more effectively, as a combination (mix) in RNAi methods (see also below). In this way, escape via antigenic drifts or shifts can be particularly effectively prevented, even in the case of existing mismatches of individual esiRNAs / ERNAs.The analogous finding applies to other sRNAs and eASOs (collectively referred to as eNAs) whose sequences could be derived from the corresponding esiRNAs / ERNAs. Summary of Application Example 1: The stated objectives were achieved. According to the invention, esiRNA / ERNA active substances or eNA active substances derived therefrom were identified that have an antiviral effect against CMV and can be used in plant protection against CMV. The identified eNAs can be used either in their unmodified form or modified at 1 to 7 nucleotide positions for protection purposes against 95% of known CMV variants. The eNAs can be used either individually or, even more effectively, as a combination (mix) in RNA silencing approaches against CMV in plant protection.Application Example 2: Double-stranded RNA drugs containing esiRNA / ERNA sequences or sequences of other related sRNAs. The task was to construct optimized double-stranded RNAs, so-called edsRNAs, for the practical application of esiRNAs / ERNAs or related sRNAs in the RNA silencing / RNAi process. These edsRNAs should accordingly contain the sequences of several esiRNAs / ERNAs and / or sRNAs derived from them (see Figure 1). Upon application in the target organism, the edsRNAs should be processed to a high degree by the DCLs / Dicer present there into the originally constituent esiRNAs / ERNAs or sRNAs, which should then become active against the targeted RNAs in the corresponding RISC.To generate a maximally effective silencing response against one or even multiple target RNAs, these edsRNAs should, as an additional property, consist of sequences of esiRNAs / ERNAs or related sRNAs that can be active in various AGO proteins and thus in various RISCs in RNA silencing / RNAi. According to the invention, the construction of edsRNAs was based on a hitherto incompletely proven hypothesis. This hypothesis assumes that DCLs / Dicers can be active at both ends (termini) of a dsRNA. The hypothesis further includes that DCLs / Dicers can be forced into "clocked processing" by the presence of so-called "pseudo-siRNA sequences" at the ends of the dsRNA. A pseudo-siRNA sequence within the meaning of the invention is therefore a double-stranded ribonucleotide sequence of any composition which, depending on the planned processing of the respective edsRNA by DCLs / Dicer, is 21, 22, 23 or 24 nt long.Pseudo-siRNA sequences should be located at the termini of the double-stranded RNA, and their presence should force the DCLs / Dicers active on this dsRNA into a timed processing cycle. Timed processing means that, depending on the position and length of the pseudo-siRNA sequences and the activity of the involved DCLs / Dicers, the endonucleolytic cleavage of the dsRNA occurs in such a way that the preferentially generated sRNAs have the same length as the pseudo-siRNAs. For example, if the pseudo-siRNA sequences are 21 nt long and DCL4 is the processing enzyme (DCL4 preferentially generates 21 nt siRNAs from a dsRNA), then 21 nt sRNAs will be preferentially generated from an edsRNA constructed in this way, in the order in which they are ranked in the sequence sequence after the pseudo-siRNAs in the edsRNA.DCL4 acts processively: Starting from the pseudo-siRNA sequences at the termini of the edsRNA, the enzyme's endonucleolytic cleavages occur sequentially. If an edsRNA is constructed in such a way that, for example, 21 nt long pseudo-siRNA sequences are immediately followed by 21 nt long esiRNA / ERNA sequences (see Figures 8-11), 21 nt long esiRNAs / ERNAs should preferentially be produced. Pseudo-siRNA sequences can also contain elements that are important for successful transcription and processing of the respective edsRNAs: These can be regions of the respective transcription promoter or terminator; but they can also be parts of a ribozyme that generates the correct 5' or 3' end of the respective RNAs (see Figures 8 and 11).The latter applies, for example, to HH ribozymes; an example was used in this application example: Here, the pseudo-siRNA sequence contains a defined number of nucleotides that are complementary to the 5' end of the ribozyme and can form its helix I and thus its functional structure through hybridization (Figure 11). The basic principle of constructing edsRNAs designed in this way is as follows (Figure 8 and following): - The sequence contains at least one pseudo-siRNA sequence, which, as explained, enables timed processing by Dicer / DCLs. In addition, the edsRNA sequence contains a number of 5' to 3' "lined up" sequences of esiRNAs / ERNAs or other sRNAs derived from esiRNAs / ERNAs, such as miRNAs, described in Figure 8 as 1-n in the sense (s) direction and n-1 in the antisense (as) direction. These sequences can come from different “eNA screens”, and accordingly the esiRNA / ERNAs orsRNAs derived therefrom can be active in different AGO / RISC (described as AZ in Figure 8). In the optimal case, the esiRNA / ERNAs or sRNAs derived therefrom that constitute an edsRNA can also be directed against different target RNAs from one or from different organisms. n in Figure 8 is a number between 2 and infinity, preferably between 2 and 100 or as described above for claim 1d. - An edsRNA can be generated in two ways: from two complementary RNA molecules or from one RNA molecule that contains two complementary subregions (Figure 8). In the second case, the two complementary subregions of the transcribed RNA are linked together by a spacer to form a hairpin.The spacer is a sequence of any composition with a minimum length of 4 nucleotides (definition as for hairpins is given above), which may contain functional regions such as ribozymes, transcription promoters or terminators, transport signals, or splice sites for the specific purpose of edsRNA construction. In this way, the spacer sequence fulfills other purposes in addition to the function of connecting the two complementary single-stranded components of a dsRNA: If it contains splice signals, for example, the spacer can be shortened by the cell's splicing machinery during RNA expression in vivo. Since the spacer, in contrast to double-stranded RNA regions, is sensitive to ribonucleases (such as the single-strand-specific RNases T1 or A), this sequence can also be completely removed by these RNases (see also Figure 8). - Transcription of RNAs can occur in vitro or in vivo.The double strand is obtained by hybridization of the complementary RNA strands (Figure 8). Transcription can occur through a variety of promoters (see Figure 11 for an example). Transcription termination can occur through any type of transcription terminator (see Figure 11 for an example). - Depending on the type of generation, the termini of the edsRNAs are either blunt or they contain an overhang (-Ü). They can be generated in different ways, e.g. via run-off transcription or termination of the respective polymerases or through the activity of ribozymes (e.g. HH or HDV ribozymes, as used in this application example) via self-splicing. - The sequences of both strands are designed in such a way that the authentic sRNA guide and passenger strand sequences are generated during processing by DCLs. The processing, which is mainly used to generate the constituent esiRNAs / ERNAs orThe presence of the pseudo-siRNA sequences and the resulting timed processing by the DCLs / Dicer ensures this. The hypothesis of 'timed processing' and thus the functionality of various edsRNA constructs constructed according to these principles was tested and confirmed according to the invention, i.e. empirically via iterative trial and error. Examples of the composition of simply designed edsRNAs that can be generated via the hybridization of two complementary RNA molecules are given in Figures 9 and 10 (SEQ ID NOs: 181 and 185 as well as 182 and 186). Such edsRNAs can be generated via in vitro transcription of classically constructed cDNAs consisting of a promoter, the coding sequence, and a terminator / run-off.Inventive examples of the composition of edsRNAs, which can be generated both in vitro and in vivo, are given by the representation of the underlying cDNA constructs (SEQ ID NOs: 200, 201, 201, 203, and 204) in Figure 11. These edsRNAs all contain a spacer that can remain intact for use or, as described above, can be shortened or degraded. Figures 12–15 demonstrate the functionality of edsRNAs designed in this way. This is exemplified by the edsRNA 'dsCMV6si21' (Figures 9, 10, and 15; SEQ ID NOs 181 and 185). This edsRNA contains six different, 21-nt-long esiRNA / ERNA sequences directed against CMV RNA 2. Three of these esiRNAs / ERNAs were shown in Application Example 1 to be active against CMV RNA 2 in the plant AGO1 / RISC; three other esiRNAs / ERNAs were previously shown to be active against CMV RNA 2 in the plant AGO2 / RISC.The functionality of the edsRNA was independent of whether it was generated in vitro or in vivo (Figure 11 and not shown) and whether this RNA had blunt or overhanging ends (-Ü). The functionality of the edsRNA was also independent of whether it was constructed from 21-, 22-, or 24-nt pseudo-siRNAs and esiRNAs / eRNAs. First, it was demonstrated that the edsRNA is processed in BYL, which has been shown to contain DCLs 4, 2, and 3 in active form (Schuck et al., 2013), into 21-, 22-, and 24-nt siRNAs, respectively. Thus, the basic processability of the designed edsRNA constructs by Dicer / DCL was demonstrated (Figure 12). By using edsRNA in in vitro slicer assays with the target RNA, it was shown that the target RNA (CMV RNA 2, for example) generates the expected cleavage products through the activity of the contained esiRNAs / ERNAs (Figure 13). This was also confirmed in a follow-up experiment.There, the siRNAs processed from an edsRNA, dsCMV6si21, in BYL (by the DCLs actively present there) were determined by NGS (RNA-seq): It is clearly evident that both the pseudo-siRNAs and the esiRNAs / ERNAs are processed from the edsRNA to a high degree (recognizable by the detectable guide or passenger strands) (Figure 14 A+B; 21 nt reads are shown in each case). The hypothesis formulated by the invention, which led to the determined structure of edsRNAs, thus proved to be correct: From dsRNAs constructed in this way, the 21 nt pseudo-siRNAs and esiRNAs / ERNAs are preferentially generated by DCL4: In total, this amounts to approximately 60% of all 21 nt siRNAs generated (Figure 14 C). According to the invention, it was shown that processing by the DCLs occurs from both ends of the dsRNA in the form of “clocked processing”.Finally, plant protection experiments demonstrated the high effectiveness (protectiveness) of using edsRNAs against a CMV challenge (infection with a lethal concentration of CMV), thus ultimately demonstrating the functionality of edsRNAs (Figure 15). Several important aspects became clear from the exemplary experiments: First, it was shown that, compared to a nonspecific dsRNA (control dsRNA 2, dsGFP; consisting of the equivalently long sequence from the GFP mRNA and its complementary RNA), an edsRNA composed of 21 nt esiRNA / ERNAs (dsCMV6si21 or dsCMV621-Ü) is 100% protective. This means that all plants treated with edsRNA remained symptom-free in the CMV challenge experiment, compared to the nonspecifically constructed dsRNA (Figure 15).-In comparison to a conventionally* constructed dsRNA, which contained a ds sequence from the CMV RNA 2 analogous to dsCMV6si21 (control dsRNA 1, dsCMV; consisting of a similarly long region of the CMV RNA2 and the complementary RNA; see Figures 9 and 10), edsRNAs had a significantly more efficient antiviral activity: * Conventional dsRNAs means that one strand of these RNAs consists of an exact copy of the targeted target RNAs and that this strand is then hybridized with a complementary RNA strand: dsRNAs constructed according to this principle are currently used in RNAi-mediated plant protection. Although the conventionally constructed dsCMV (control dsRNA 1) showed a certain degree of protection compared to dsGFP (control dsRNA 2), this protection did not last over the entire test period of 35 dpi.In comparison, as mentioned above, the edsRNA composed of esiRNA / ERNAs provided 100% protection throughout the entire test period (Figure 15). It is important to note that the dsCMV used as a control also contained two of the sequences previously characterized as esiRNAs / ERNAs (shown in Figure 9). Thus, this control very well reflected the situation of treatment with a conventional dsRNA, which contains few, if any, esiRNA / ERNA sequences (shown schematically in Figure 1). - edsRNAs generating 21 nt esiRNAs / ERNAs were most efficiently protective against CMV; EdsRNAs producing the same esiRNAs / ERNAs but as 22 nt versions were less protective: In contrast to the 21 nt edsRNA, the 22 nt edsRNA did not show 100% protection over the entire test period.Compared to the conventionally constructed dsCMV, the protection provided by the edsRNA generating 22 nt esiRNAs / ERNAs was significantly more pronounced (Figure 15). The same applies to a 24 nt esiRNA / ERNA generating edsRNA (not shown). When the 170 nt long single-stranded components of the dsRNAs (dsCMV6si21 or dsCMV621-Ü and dsCMV) were tested in protection experiments, they showed no protection (Figure 15 C). This experiment, conducted as a further control, demonstrated that the edsRNAs used are indeed active exclusively in the double-stranded form. The observed protective effect must therefore be based on the (time-controlled) processing of the edsRNAs into esiRNA / ERNAs by the plant DCLs in vivo.In other words, it was thus possible to rule out the possibility that 21, 22, or 24 nt long segments from the single-stranded components of the dsRNAs would randomly associate with the target RNAs during the experiment, thus triggering AGO / RISC-mediated slicing and thus protection. Summary of Application Example 2: According to the invention, completely novel designed and constructed edsRNA agents were developed that can be easily produced via transcription in vitro or in vivo and from which, via processing by Dicer / DCLs, significant quantities of the various constituent sRNAs are generated. EdsRNAs constructed in this way can be used as efficient antipathogenic agents.Application Example 3: Nucleic acid agents against Meloidogyne incognita. esiRNAs / ERNAs were identified in BYL using the described method with the AGO2 protein from Nicotiana benthamiana (Nb) against three mRNAs from Meloidogyne incognita target genes (SEQ ID NOs: 191 to 193). These target genes encode the proteins "splicing factor," "actin-4," and "integrase." Along with other factors, these proteins were assumed to play an essential role in the life cycle of Meloidogyne incognita (see also above). The respective gene and target RNA sequences (see appendix) were generated as follows. In the case of actin-4: The sequence was determined using the accession number of actin-4 for C. elegans at https: / / wormbase.org / / #012-34-5. This was used to perform a sequence comparison (Blast N) in the database https: / / meloidogyne.inrae.fr / . This resulted in the sequence of the predicted cDNA in M. incognita being determined.This was confirmed by a sequence comparison of the deduced protein sequence (Blast P) in the NCBI database (National Center for Biotechnology Information) and cloned. In the case of splicing factor and integrase, EST (expressed sequence tag) sequences from M. incognita (AW828516 and AW871671, respectively) from the NCBI database were used. These were used for a Blast N in the database https: / / meloidogyne.inrae.fr / . After the predicted cDNA sequences were found, a Blast P was performed on the deduced protein sequences, which confirmed their homologousness to the sequences of splicing factor and integrase from C. elegans. These cDNAs were cloned accordingly. The esiRNAs / ERNAs summarized in Table 7 (SEQ ID NO in the supplement to Table 7) were identified and classified according to the characteristics defined above. The name is “siR”, “MI” for M.incognita, the respective mRNA (SPF, splicing factor; INT, integrase; ACT, actin 4), and the position of the RNA to which the 5' nucleotide of the siRNA guide strand is complementary). They were validated in various ways (see Figures 16 and 17). - Standardized slicer assays according to the protocol described above. The esiRNAs / ERNAs and derived edsRNAs (Figures 8 and 11) were validated in slicer assays with NbAGO2 with regard to their cleavage (slicing) activity of the respective target RNAs in vitro. All 14 of the siRNAs identified with the "eNA screen" showed induced hydrolysis of the target RNAs, comprising more than 25% of the original quantity of these target RNAs (summarized in Table 7). - In vivo. Second, the efficiency of cleavage of the respective mRNA after uptake of the siRNAs was tested in vivo (i.e., in animals). For this purpose, M. incognita J2 animals were obtained, and 10,000 of them were suspended in 40 µl of water includingThe nematodes were incubated (soaked) with 50–200 ng / µl RNA for 24 hours to allow uptake of the RNAs. The siRNA siR gf698 (siR GFP) was used as a negative control. Subsequently, the nematodes were disrupted using a standard procedure, total RNA was extracted, and the cleavage of the respective target mRNA was examined using appropriate primers and quantitative real-time RT-PCR (qRT-PCR). For gene-specific reverse transcription (RevertAid Reverse Transcriptase, ThermoFisher) to cDNA, also using a standard procedure, approximately 500 ng of total RNA or 1 / 5 diluted cDNA was used as the PCR template. The M. incognita GAPDH gene (Minc3s07075g40689) was used as the reference gene. The calculation of the normalized expression rates (NER), which reflects the measurable quantity of target mRNA originally used in the assay remaining after cleavage (see also Figure 14), followed mathematical method 2. -ddCtusing the mean Ct value of the reference gene. - In vivo / in planta. Finally, the ability of the esiRNAs / ERNAs to suppress the entire nematode life cycle in planta was tested. In a first form of the experiments, J2 animals were soaked in water-soluble RNAs or control RNA for 24 hours, as described above. Subsequently, two-week-old tomato plants were infected with the treated nematodes according to a standard protocol (500 animals per plant). It was investigated whether this treatment led to a reduction in egg laying after infection or to reduced pathogenesis (particularly gall formation) of the infected plants. In a second form of these experiments, infection studies were conducted on fresh seedlings. For this purpose, tomato seeds were surface-sterilized by soaking in 70% ethanol.After removing the ethanol, the seeds were treated with a solution containing 30% (v / v) NaOCl and 0.02% Triton X-100 and incubated for 20–30 minutes. They were then washed with sterile distilled water and placed in Petri dishes containing approximately 6 mm of 0.6% Phytagel pH 6.4 in ¼ MS (Murashige and Skoog Medium) including 0.5% sucrose. Ten seeds were randomly distributed in each Petri dish, which was then sealed with Nescofilm and kept at 28°C with a 16-hour light / 8-hour dark cycle. Seven to ten days after sowing, each seedling was inoculated with 100–200 sterile and soaked J2 seeds. The J2 animals were surface sterilized for 5 minutes in a solution containing 0.004% mercuric chloride, 0.004% sodium azide, and 0.002% Triton X-100, washed with sterile water, and suspended in 0.1% agarose. Soaking was performed as described above.The inoculated seedlings were grown under the conditions described above. The infection process was monitored by examining gall formation three weeks after inoculation. The esiRNAs / ERNAs listed in Table 7 had a significant silencing or nematicidal effect in the aforementioned tests (see Figures 16 and 17). Summary of Application Example 3: The stated objectives were achieved. According to the invention, esiRNA / ERNA active substances or eNA active substances derived therefrom were identified that have a nematicidal effect against M. incognita and can be used in plant protection against M. incognita. The identified eNAs can be used either in their unmodified form or modified in 1 to 7 nucleotides for protection purposes against all known M. incognita variants. The eNAs can be used either individually or, even more effectively, as a combination (mix) in RNA silencing approaches in plant protection against M.incognita. Furthermore, edsRNAs containing the sequences of identified esiRNAs / ERNAs or other sRNAs derived from them can be used in plant protection against M. incognita. Application example 4: Nucleic acid agents against Botrytis cinerea. esiRNAs / ERNAs were identified and classified in BYL using the described method with the AGO1 protein from Colletotrichum graminicula (C. graminicula is, like B. cinerea, a plant pathogenic fungus) against various mRNAs of B. cinerea target genes. Three of the target RNAs (SEQ ID NOs: 197, 199, 198); were selected due to the fact that the respective encoded proteins, “cytochrome P450 monooxygenase” (Erg27), “chitin synthase 1” (CHS1) and “elongation factor 2” (EF2), are already known as target molecules of various fungicides (see introduction to B. cinerea).Three additional target RNAs (SEQ ID NOs: 194, 195, 196) were selected because the proteins they encode, “Vacuolar protein sorting 51” (VPS51), “Dynactin” (DCTN1), and “Suppressor of actin” (SAC1), are involved in the vesicular transport pathway in the fungus and are essential virulence factors of B. cinerea during interaction with plant hosts. The cDNAs for these genes were generated and cloned from an mRNA preparation. The mRNA preparation was prepared from B. cinerea-infected Arabidopsis thaliana plants using a standard procedure. The labeled esiRNAs / ERNAs summarized and listed in Table 8 were identified (SEQ ID NO in “Supplement to Table 8”). The candidates are designated “siR,” “BC” for B.cinerea, the respective RNA (ERG - Erg 27; CHS - Chitin synthase 1; EF - Elongation factor 2; VPS - Vacuolar protein sorting 51; DCTN - Dynactin 1; SAC - Suppressor of actin), and the position of the RNA to which the 5' nucleotide of the siRNA guide strand is complementary. They were validated as follows: - Standardized slicer assays according to the protocol described above. For this purpose, the RNAs were tested in vitro with C. graminicula AGO1 for the cleavage (slicer) activity of the respective target RNAs: 24 of a total of 30 siRNAs identified with the "eNA screen" showed induced hydrolysis of the respective target RNA, comprising more than 25% of the original quantity of this target RNA (Figure 18 and Table 8). - In vitro fungal growth experiments. B. cinerea B05.10 was cultivated on fruit. After the fungus had sporulated for five days, the spores were collected and incubated in appropriate medium to a final concentration of 1x10. 5spores / ml (standard procedure). Subsequently, spore germination was initiated by adding phosphate. To ensure uniform germination, 10 µl of 1M phosphate buffer, pH 6.4, was added to 990 µl of spore solution. The effects of the esiRNAs / ERNAs on the growth of B. cinerea were tested in vitro on potato dextrose agar (PDA) plates. From a spore solution with a final concentration of 1x10 5 / ml, 10 µl were added to the center of a plate. For treatment, 400–8000 ng of RNA were added to the spore solution and then continuously added every 12 h. In addition to the B. cinerea-specific esiRNAs / ERNAs and edsRNAs, siR gf698 (siR GFP) and water were added to the spores as controls. The growth dynamics under the influence of the RNAs compared to the controls were assessed by measuring the fungal colony diameter (ImageJ software) on days 1, 2, 3, and 5, respectively, after inoculation. - In vivo / in planta fungal growth experiments. Here, the ability of the esiRNAs / ERNAs to suppress the entire life cycle of B. cinerea in planta was tested. For this purpose, RNAs were added to the solution of induced spores (1x10 5 / ml, see above) and the solution was incubated for one and a half hours at room temperature. For infection, A. thaliana leaves were moistened with a 10 µl drop of the incubation solution. The plants were then kept in chambers with high humidity for two days; afterward, the size of the lesions caused by the fungus was compared (ImageJ software) with those of control plants infected with spores containing the siR gf698 control or water (see also Figure 19). To further determine fungal growth, tissue from the leaf sections was removed and B. cinerea DNA was quantified by qPCR using the standard curve method. The B. cinerea actin gene and a control gene from a plasmid preparation spiked into the plant samples were detected.The plasmid control gene was used to estimate the efficiency of the DNA extraction process and to normalize cut A amplification. Finally, the amount of B. cinerea DNA was determined by interpolating the normalized cut A values ​​on the standard curve. - By transcript analysis: To evaluate the silencing of target RNAs in B. cinerea, mRNA expression analysis was performed using quantitative real-time RT-PCR (qRT-PCR). For this purpose, 1 x 10 5Spores were taken up in 2 mL of liquid medium, and RNA was added (see above). The samples were then cultured at room temperature with shaking for 24, 48, and 72 hours. RNA extraction from the fungal sample was performed using TRIzol according to the manufacturer's instructions. qRT-PCR was performed as described in Application Example 3 (see also Figure 19). The esiRNAs / eRNAs listed in Table 8 had a significant silencing effect in vitro (Figure 19) and fungicidal effect (Figure 19). As Figure 19 also shows, treatment in planta, even with nonspecific NAs, had a slight fungicidal effect, but treatment with eNAs specifically directed against target RNAs had a significantly stronger fungicidal effect. Summary of Application Example 4: The tasks were solved. According to the invention, esiRNA / ERNA active substances or eNA active substances derived therefrom were identified that are effective against B.cinerea have a nematicidal effect and can be used in plant protection against B. cinerea. The identified eNAs can be used either in their unmodified form or modified by 1 to 7 nucleotides for protection purposes against all known B. cinerea variants. The eNAs can be used either individually or, even more effectively, as a combination (mix) in RNA silencing approaches for plant protection against B. cinerea. In addition, edsRNAs, which contain the sequences of identified esiRNAs / ERNAs or other sRNAs derived from them, can be used in plant protection against B. cinerea.

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Claims

1 Patent claims 1. Nucleic acid for protecting plants against the plant pathogens Cucumber mosaic virus, Meloidogyne incognita and Botrytis cinerea, characterized in that a. the nucleic acid is a small interfering RNA (siRNA) consisting of 21, 22, 23 or 24 base pairs and containing two single-stranded RNAs selected from a guide strand and a passenger strand, wherein the guide strand and the passenger strand are selected from the group consisting of the nucleic acids with SEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, 47-51, 53, 55-65, 69-70, 73, 75-85, 89-90, 93-120, 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180; or b. the nucleic acid is an siRNA according to group a, wherein at least one of the single-stranded RNAs selected from a guide strand and a passenger strand has changes in 1 to 7 positions of the nucleotide sequence; or c.the nucleic acid is a small RNA selected from an siRNA and a micro RNA (miRNA), the RNA double strand of which consists of complementary or partially complementary nucleic acids from group a. and / or group b.; or d. the nucleic acid is a double-stranded RNA containing nucleotide sequences of at least two siRNAs or sRNAs from groups a, b or c.; or e. the nucleic acid is a single-stranded DNA consisting of 12 to 25 nucleotides and containing a sequence of 12 or more nucleotides that are homologous to one of the nucleotide sequences of the single-stranded RNAs from groups a. or b.; or f. the nucleic acid is a single-stranded DNA according to group e. which has changes at 1 to 7 positions of the nucleotide sequence.wherein the nucleic acid is provided for the protection of plant pathogens with a method for the targeted identification of effective small interfering RNAs (esiRNAs / ERNAs) and sRNAs derived therefrom, as well as effective antisense DNA oligonucleotides (eASO) of different lengths, collectively referred to as effective nucleic acids (eNAs), comprising the steps (i) an RNA which has been selected as a target for RNA silencing (RNAi) is produced by in vitro transcription and converted into small interfering RNAs (siRNAs) in cytoplasmic extracts of plant cells by the endogenous Dicer-like proteins (DCL);. 2 (ii) a DCL-generated siRNA pool is formed from the RNA used, and the siRNAs contained in this pool are determined by RNA-seq analysis; (iii) a messenger RNA (mRNA) of an Argonaute (AGO) protein synthesized via in vitro transcription is added to the cytoplasmic plant cell extract, the mRNA being constructed in such a way that it encodes the AGO protein in question with a tag; (iv) AGO protein molecules are formed via in vitro translation, which form RNA-induced silencing complexes (RISC) complexes with the DCL-generated siRNAs present; (v) siRNA-loaded AGO / RISC are immunoprecipitated from the BYL via a tag, and the bound siRNA guide strands are determined by RNA-seq analysis; (vi) by comparing the RNA-seq data with those from step (ii) those siRNAs that are enriched in AGO / RISC are identified;(vii) subsequently produced synthetically and tested for functionality in a slicer assay with labelled target RNA and (viii) in this way esiRNAs / ERNAs are identified and sRNAs derived therefrom, as well as eASO, collectively referred to as eNAs, are determined; characterized in that I. to form the RISC in step (vii), translation is carried out in a reaction solution containing 50% (v / v) BYL, 0.5 pmol of the mRNA of the AGO protein to be used in the presence of 10-100 nM of the synthetic siRNA to be characterized and a 10-fold excess (0.1-1 µM) of a competitor siRNA (e.g. siR gf698, selected from the group consisting of SEQ ID NO: 205, 206, 207, and 208;);II. after an incubation period of 2.5 h at 25°C per reaction in step I, 3.4 pmol of a non-specific mRNA (e.g., encoding the firefly luciferase protein, SEQ ID NO: 209 Schuck et al., 2013) as additional competitor RNA and 10 fmol of the target RNA, with the target RNA being labeled, are added, and the reaction mixtures are incubated again for 15 min at 25°C; III. during the incubation in step II, the target RNA is cleaved by the formed AGO / RISC; 3 IV. After gel electrophoresis of the extracted RNA, the quantity of target RNA remaining, or the resulting cleavage products, compared to a control reaction (conducted without siRNA), is quantified by measuring the band intensities (ImageQuantTL or ImageJ); V. Classification as esiRNA / ERNAs is carried out based on the measured cleavage activity (slicer activity) of the RISC formed with this siRNA on the target RNA; VI. EsiRNA / ERNA are selected that endonucleolytically convert at least 25% or more of the quantity of target RNA originally used in process step II into cleavage products. 2.Nucleic acid according to claim 1, characterized in that the pathogen is Cucumber mosaic virus (CMV) and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid which is directed against a target RNA of the CMV, wherein the target RNA of the CMV is selected from the target RNAs with SEQ ID NO: 189 and 190.

3. Nucleic acid according to claim 1 or 2, characterized in that the pathogen is Cucumber mosaic virus (CMV) and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid which is selected from the group consisting of the nucleic acids with SEQ ID NO: 1-4, 6-11, 14-17, 21-25, 27-30, 32-37, 40-43, 47-51, 53, 55-66, 69-70, 73, 75-86, 89-90 is selected. 4.Nucleic acid according to claim 1, characterized in that the pathogen is Meloidogyne incognita and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid directed against a target RNA of Meloidogyne incognita, wherein the target RNA of Meloidogyne incognita is selected from the target RNAs with SEQ ID NOs: 191, 192, and 193.

5. Nucleic acid according to claim 1 or 4, characterized in that the pathogen is Meloidogyne incognita and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid selected from the group consisting of nucleic acids with SEQ ID NOs: 93 to 120. 6.Nucleic acid according to claim 1, characterized in that the pathogen is Botrytis cinerea and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid directed against a target RNA of Botrytis cinerea, wherein the target RNA of Botrytis cinerea is selected from the target RNAs with SEQ ID NO: 194, 195, 196, 197, 198 and 199. 4 7. Nucleic acid according to claim 1 or 6, characterized in that the pathogen is Botrytis cinerea and contains the ribonucleotide or deoxyribonucleotide sequence of at least one nucleic acid selected from the group consisting of nucleic acids with SEQ ID NO: 124, 126-132, 134-138, 140-150, 154, 156-162, 164-168 and 170-180.

8. Nucleic acid according to claim 1, characterized in that the nucleic acid is a double-stranded RNA and this double-stranded RNA contains nucleotide sequences consisting of pseudo-siRNA sequences and sequences of at least two siRNAs or sRNAs according to claim 1 a, b or c.

9. Nucleic acid according to claim 8, characterized in that the nucleic acid has blunt or overhanging ends.

10. Nucleic acid according to claim 8 or 9, characterized in that the nucleic acid contains a spacer. 11.Nucleic acid according to any one of claims 8 to 10, characterized in that the pseudo-siRNA sequences and spacers in the nucleic acid contain elements selected from transcription promoters, transcription terminators, transport signals, splice sites, and ribozymes.

12. Nucleic acid according to any one of claims 8-11, characterized in that the nucleic acid is selected from the group consisting of nucleic acids with SEQ ID NO: 181, 182, 185, 186, and 200 to 204. 13.Nucleic acid according to one of the preceding claims, wherein the nucleic acid has one or more chemical modifications, characterized in that the chemical modifications are selected from conjugates such as GalNac, base modifications such as 5-methylcytosine, 2'-sugar modifications such as 2'-O-methyl, 2'-fluoro, 2'-O-methoxyethyl (2'-MOE), cETBNA ((S)-linked ethyl bicyclic), other sugar modifications such as "locked" (LNA) or "unlocked" (UNA), "backbone" modifications such as phosphorothioate (PS) or "peptide nucleic acids" (PNA) and sugar phosphate modifications such as morpholino / PMO (phosphorodiamidate morpholino).

14. Composition for use in pest control in plants comprising one or more nucleic acids according to one of claims 1 to 13 and optionally one or more carrier substances and / or excipients. 15.Use of a nucleic acid or composition according to any one of claims 1 to 14 in plants for the prophylaxis and / or treatment against infestation and / or infections by pathogens.

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