Use of a substance that inhibits lnc-ALOX12 in the preparation of an influenza virus inhibitor

Abstract

The present invention relates to the field of biomedicine, and discloses the use of substances that inhibit lnc-ALOX12 in the preparation of influenza virus inhibitors. The present invention for the first time provides that a long non-coding RNA lnc-ALOX12 participates in the replication process of influenza virus as a positive regulatory factor. IAV infection can specifically promote the expression of lnc-ALOX12. Silencing of lnc-ALOX12 can significantly inhibit the transcriptional replication of viral RNA and regulate the nuclear entry of influenza virus PB2 protein. lnc-ALOX12 is involved in host adaptation mediated by PB2 mutants. The present invention reveals that lnc-ALOX12 plays an important role in the replication process of influenza virus and its cross-species transmission, providing a new basis for the development of host lncRNA as an antiviral drug target.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and more particularly, to the use of substances that inhibit lnc-ALOX12 in the preparation of influenza virus inhibitors. Background Art

[0002] Influenza virus can cause acute respiratory infectious diseases. Among them, influenza A virus (IAV) poses the greatest threat, and it is prone to mutate. It is a highly contagious and highly pathogenic virus, and both humans and various animals are susceptible. For a century, seasonal influenza every year and multiple influenza pandemics have posed a serious threat to human life and health and caused significant economic losses. At present, the main means for preventing and treating influenza virus clinically are vaccines and anti-influenza drugs. However, due to the extremely strong recombination and antigen drift ability of influenza virus, the lag of new virus-specific vaccines and the continuous emergence of drug-resistant virus strains have made the prevention and control situation of new viruses increasingly serious. Influenza virus is an important human pathogen and poses a major threat to global public health and the economy. The role of host lncRNAs in IAV infection has also received extensive attention.

[0003] Long non-coding RNA (lncRNA) refers to a transcript with a length exceeding 200 nucleotides and has a low potential for encoding proteins. Compared with mRNA, lncRNA generally shows a more specific expression profile, lower abundance and conservation. LncRNA plays a role in various important physiological processes such as genomic imprinting, immune response, and nucleocytoplasmic transport.

[0004] The influenza virus RNA genome consists of eight segments of negative-sense single-stranded RNA, which are coated by nucleoprotein (NP) and a heterologous polymerase complex (PB1, PB2, and PA subunits) to form a viral ribonucleoprotein (vRNP) complex, which is an important functional unit for IAV genome transcription and replication. There is evidence that the PB1-PA dimer directly binds to RanBP5 and is transported into the nucleus through a non-classical pathway. PB2 and NP enter the nucleus through a classical pathway that directly interacts with the importin-α / β1 dimer. Existing studies have shown that the adaptation of the viral polymerase to the nuclear import mechanism is an important mechanism for the cross-species transmission of avian influenza virus. Some adaptive mutations of the viral polymerase, such as the PB2 subunit, especially at positions 627 and 701, and N319K in NP, have been confirmed to be related to the adaptation of avian IAV to mammals, and these mutations enhance the binding of these proteins to importin-α. However, the exact regulatory mechanism of how host factors regulate the nuclear import of vRNPs remains to be clarified. Whether other cytokines, especially lncRNA, are involved in the adaptation of the viral polymerase to the nuclear import mechanism and mediate the interspecies transmission of influenza virus needs to be further explored. Summary of the Invention

[0005] The object of the present invention is to provide the use of a substance that inhibits lnc-ALOX12 in the preparation of an influenza virus inhibitor.

[0006] To achieve the object of the present invention, the present invention provides a human lncRNA with an unreported function, named lnc-ALOX12. Lnc-ALOX12 includes two transcripts, lnc-ALOX12-1 and lnc-ALOX12-2, which are transcribed from 14 exons of nucleotides 6,891,943 - 6,954,939 of 17p13.1 of the hg38 genome (NONHSAT145301.2 in the NONCODE v5 database (http: / / v5.noncode.org / index.php)) and nucleotides 6,937,274 - 6,954,409 (NONHSAT145307.2 in the NONCODE v5 database), respectively.

[0007] In a first aspect, the present invention provides the use of a substance that inhibits lnc-ALOX12 in the preparation of an influenza virus inhibitor.

[0008] The lnc-ALOX12 is a long non-coding RNA derived from humans, and the sequences of its two transcripts are shown as SEQ ID NO:1 (lnc-ALOX12-1) and SEQ ID NO:2 (lnc-ALOX12-2).

[0009] In the present invention, the influenza virus is an influenza A virus.

[0010] Preferably, the substance that inhibits lnc-ALOX12 is esilnc-ALOX12, and its target sequence acting on lnc-ALOX12 is shown as SEQ ID NO:3.

[0011] In a second aspect, the present invention provides an influenza virus inhibitor, and its active ingredient is the above-mentioned substance that inhibits lnc-ALOX12.

[0012] By means of the above technical solution, the present invention has at least the following advantages and beneficial effects:

[0013] The present invention discloses for the first time that a long non-coding RNA lnc-ALOX12 participates in the replication process of influenza virus as a positive regulatory factor. IAV infection can specifically promote the expression of lnc-ALOX12. Silencing of lnc-ALOX12 can significantly inhibit the transcriptional replication of viral RNA and regulate the nuclear import of influenza virus PB2 protein. lnc-ALOX12 is involved in host adaptation mediated by PB2 mutants. The present invention reveals that lnc-ALOX12 plays an important role in the replication process of influenza virus and its cross-species transmission, providing a new basis for developing host lncRNA as an antiviral drug target. Brief Description of the Drawings

[0014] Figure 1 In the preferred embodiment of the present invention, IAV infection induces the expression of lnc-ALOX12 and is independent of IFN. A and B: HEK293T cells were infected with WSN for 24 hours (A) or infected with different multiplicities of infection (moi) for different times (B), and qRT-PCR was performed to detect the expression of lnc-ALOX12 (upper panel) and viral RNA levels (lower panel). C: The levels of lnc-ALOX12 (left panel) and viral RNA (right panel) in A549 cells infected with different influenza virus strains for 24 hours were determined by qRT-PCR. D: After A549 cells were treated with IFN-α (1,000 IU / mL) for different times, the levels of lnc-ALOX12 and MxA mRNA were determined by qRT-PCR. E: The levels of lnc-ALOX12 and IFN-β mRNA in 293T cells transfected with different amounts of poly(I:C) were detected by qRT-PCR.

[0015] The data in A-E are Mean ± SD. p≤0.05, p≤0.01, NS, not significant difference (one-way ANOVA).

[0016] Figure 2In a preferred embodiment of the present invention, lnc-ALOX12 silencing inhibits IAV infection. A-C: HEK293T-Gluc cells were transfected with 10, 20, 40 nM esiEGFP or esilnc-ALOX12 respectively, and then infected with WSN (MOI = 0.5) for 24 hours. The knockdown efficiency of Lnc-ALOX12 was detected by qRT-PCR (A), and the infectivity of the virus was analyzed by measuring the Gluc reporter activity (B). The progeny virus titer was determined by the TCID50 method (C). D: The cell viability of HEK293T cells transfected with 10, 20, 40 nM esiEGFP or esilnc-ALOX12 for 48 hours was determined by the CCK8 assay. E: Different doses of lnc-ALOX12 were transfected into HEK293T-Gluc cells, and the infectivity of the virus was analyzed by measuring the Gluc reporter activity (left panel), and the expression level of lnc-ALOX12 was determined by qRT-PCR (right panel).

[0017] Data in A-E are Mean ± SD. p ≤ 0.05, p ≤ 0.01, NS, not significant (two-tailed Student's t-test (A-D) and one-way ANOVA with Dunnett's post-test (E)).

[0018] Figure 3 In a preferred embodiment of the present invention, lnc-ALOX12 silencing inhibits viral RNA transcription and replication. A: HEK293T cells were transfected with esilnc-ALOX12 or esiEGFP and then infected with WSN (MOI = 3). Immunofluorescence staining of viral NP (red) and cell nuclei (blue) was performed at different time points. B: In HEK293T cells transfected with esiEGFP or esilnc-ALOX12, the RNP recombinant plasmid (PB1, PB2, PA, NP) and the polI-luc reporter plasmid were transfected again. The effect of lnc-ALOX12 on the IAV replicon system was studied by measuring luciferase activity. C: HEK293T cells were transfected with esiEGFP or esilnc-ALOX12 and then infected with WSN (MOI = 0.5) for 24 hours, and the levels of viral NP mRNA / vRNA / cRNA were determined by qRT-PCR.

[0019] Data in B and C are Mean ± SD. p ≤ 0.05, p ≤ 0.01, NS, not significant (one-way ANOVA with Dunnett's post-test (B), two-tailed Student's t-test (C)).

[0020] Figure 4 For the preferred embodiment of the present invention, lnc-ALOX12 silencing inhibits viral PB2 nuclear import. A: HEK293T cells were transfected with esiEGFP or different amounts of esilnc-ALOX12, and then co-transfected with plasmid DNA encoding vRNP subunits (PB1, PB2, PA, NP, and PolI-luc). Western blotting was used to analyze the protein levels of viral PA, PB1, and PB2. B: HEK293T cells were transfected with esiEGFP or esilnc-ALOX12, and then co-transfected with plasmid DNA encoding vRNP (PB1, PB2, PA, NP, and PolI-luc). After treatment with DMSO or MG132 for 6 h, cells were fractionated into cytoplasm and nucleus, and Western blotting was used to analyze the levels of viral PB2 in whole cell, cytoplasm, and nucleus. GAPDH protein was used as a cytoplasmic marker, and p84 protein was used as a nuclear marker. C: HEK293T cells were transfected with esiEGFP or esilnc-ALOX12, and then co-transfected with plasmid DNA encoding PB1, PB2, PA, NP, and PolI-luc, and harvested after treatment with MG132 for 6 h. Cell lysates were immunoprecipitated and analyzed by Western blotting using control antibody (IgG), anti-importin α1, or anti-importin β antibody. D: PLA technology was used to analyze the effect of lnc-ALOX12 on the co-localization of PB2 and importin. Randomly selected cell fields were statistically analyzed for the difference in red fluorescence spots (n = 30, p ≤ 0.001, two-tailed Student's t-test).

[0021] Figure 5In the preferred embodiment of the present invention, nc-ALOX12 is involved in host adaptation mediated by the PB2 mutant. A: The activities of viral polymerases containing PB2 (WSN-PB2) and its mutants (avian-PB2 and mammal-PB2) were determined by luciferase activity assay. B: The binding of lnc-ALOX12 to PB2 (WSN-PB2) and its mutants (avian-PB2 and mammal-PB2) was detected by RIP technology. C: The effect of knocking down lnc-ALOX12 on the activities of viral polymerases containing PB2 (WSN-PB2) and its mutants (avian-PB2 and mammal-PB2) in human 293T cells. D: The effect of knocking down chicken chlnc-ALOX12 on the activities of viral polymerases containing PB2 (WSN-PB2) and its mutants (avian-PB2 and mammal-PB2) in chicken DF-1 cells. E: The effect of overexpressing chicken chlnc-ALOX12 on the activities of viral polymerases containing WSN-PB2 or avian -PB2 in human 293T cells. F: In human 293T cells, the effect of overexpressing chicken chlnc-ALOX12 on the interaction between importin and WSN-PB2 or avian -PB2 was analyzed by co-immunoprecipitation technology. G: In chicken DF-1 cells, the effect of knocking down chicken chlnc-ALOX12 on the interaction between importin and WSN-PB2 or avian -PB2 was analyzed by co-immunoprecipitation technology.

[0022] (A-E) The data are Mean ± SD. p≤0.05, p≤0.01, p≤0.001, NS, not significant (two-tailed Student's t-test (C-E)). Detailed implementation mode

[0023] The following examples are used to illustrate the present invention, but not to limit the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well-known to those skilled in the art, and the raw materials used are all commercially available products.

[0024] The cell culture medium used in the following examples was DMEM medium containing 10% FBS. The influenza strain A / WSN / 33 was generated by virus rescue using an 8-plasmid system. Influenza virus A / WSN / 33 (H1N1) was generated by transfecting 8 plasmids (each plasmid encoding an IAV RNA segment) into HEK293T cells according to the method described by Hoffmann et al. (Hoffmann, E., Neumann, G., Kawaoka, Y., Hobom, G., and Webster, R.G. (2000). A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A 97, 6108-6113. 10.1073 / pnas.100133697.), followed by co-culture with MDCK. Influenza viruses A / PR / 8 / 34 (H1N1), B / Beijinghaidian / 1386 / 2013, and B / Massachusetts / 02 / 2012 (provided by Dr. Yuelong Shu of the National Influenza Center, China), and A / Beijing / 30 / 95 (H3N2) (provided by Dr. Wenjie Tan of the Chinese Center for Disease Control and Prevention) were propagated in chicken embryos.

[0025] 293T, A549, MDCK, and DF-1 cells were purchased from American Type Culture Collection (ATCC) (Manassas, VA). The 293T-Gluc cell line was generated by transfecting plasmid DNA pLenti6-Gluc to constitutively express the negative-strand RNA of the secreted luciferase (Gluc) gene. Gluc reporter gene activity was used to evaluate the level of IAV infection. All cells were cultured in DMEM (Gibco, Carlsbad, CA, USA) containing 10% fetal bovine serum (FBS; Gibco) at 37 °C in a 5% carbon dioxide incubator, except for DF-1 cells which were cultured at 39 °C.

[0026] Example 1 Specific induction of lnc-ALOX12 expression by IAV infection

[0027] We first evaluated the effect of IAV infection on the expression level of lnc-ALOX12. HEK293T cells were infected with IAV, and the levels of intracellular lnc-ALOX12 and viral RNA were measured by RT-qPCR 24 hours later. The results are as Figure 1As shown in (A and B), with the increase of viral RNA dose and time after infection, the level of lnc-ALOX12 was also upregulated. Similarly, in cells infected with other IAVs (A / Beijing / 30 / 95 (H3N2) and A / PR / 8 / 34 (H1N1)), lnc-ALOX12 was induced to express, while in cells infected with influenza B virus (B / Beijinghaidian / 1386 / 2013 and B / Massachusetts / 02 / 2012), lnc-ALOX12 was not induced to express ( Figure 1 , C). Notably, we found that treatment with IFN-α ( Figure 1 , D) or poly(I:C) ( Figure 1 , E) could upregulate the mRNA levels of the positive control genes MxA ( Figure 1 , D) and IFN-β ( Figure 1 , E), but did not affect the level of lnc-ALOX12 in cells. These data indicate that lnc-ALOX12 can be specifically induced to express by IAV infection, rather than an immune response of the host to viral infection.

[0028] Example 2 Silencing of lnc-ALOX12 Inhibits IAV Infection

[0029] In this example, two esiRNAs (endoribonuclease prepared siRNA), named esilnc-ALOX12 and esiEGFP respectively, were used. esilnc-ALOX12 is an esiRNA for silencing the human lnc-ALOX12 gene. esilnc-ALOX12 targets two transcripts of human lnc-ALOX12, lnc-ALOX12-1 and lnc-ALOX12-2. The target sequence of esilnc-ALOX12 acting on human lnc-ALOX12 (esilnc-ALOX12 cDNA target sequence) is shown as SEQ ID NO:3. esilnc-ALOX12 is a product of Sigma Company, and its catalog number is EHNC006181.

[0030] esiEGFP is an esiRNA used as a negative control for esilnc-ALOX12. It targets EGFP and is an esiRNA for silencing the EGFP gene. esiEGFP is a product of Sigma Company, and its catalog number is EHUEGFP.

[0031] IAV promotes the expression of lnc-ALOX12. We investigated whether the level of lnc-ALOX12 affects IAV replication. First, esiEGFP or esilnc-ALOX12 was transfected into 293T cells by reverse transfection at concentrations of 10 nM, 20 nM, and 40 nM, respectively. After 24 h, the cells were infected with influenza virus A / WSN / 33 (H1N1) at an MOI of 0.5. After 24 h, the cells and supernatants were collected. The knockdown effect of esiRNA on endogenous lnc-ALOX12 in the cells was detected by real-time fluorescence quantitative PCR (RT-qPCR). At the same time, the infection level of the virus and the titer of progeny virus were reflected by measuring the Gluc (secreted luciferase) activity in the cell supernatant and the TCID50 value, respectively. The results are as Figure 2 shown. Esilnc-ALOX12 (20 nM and 40 nM) significantly reduced the expression of lnc-ALOX12 ( Figure 2 , A). Compared with the control cells, both the Gluc activity in the cell supernatant and the virus titer decreased with the decrease in the level of lnc-ALOX12 ( Figure 2 , B and C). At the same time, the results of the cytotoxicity experiment showed that transfection with esilnc-ALOX12 did not affect cell viability compared with transfection with esiEGFP ( Figure 2 , D). In summary, these results indicate that esiRNA-mediated lnc-ALOX12 silencing inhibits the IAV replication process, and this inhibitory effect is not caused by cytotoxicity.

[0032] To further confirm the effect of lnc-ALOX12 on IAV replication, we transfected 293T-Gluc cells with DNA overexpression plasmids expressing lnc-ALOX12-1 and lnc-ALOX12-2, and then infected them with IAV (A / WSN / 33). The level of lnc-ALOX12 was measured by RT-qPCR, and the replication of IAV was analyzed by Gluc activity. The results showed that overexpression of lnc-ALOX12 had no effect on IAV replication ( Figure 2 , E), indicating that the endogenous lnc-ALOX12 level induced by IAV infection is almost sufficient to meet the needs of virus replication.

[0033] Example 3 Gene silencing of lnc-ALOX12 inhibits the transcriptional replication of viral RNA

[0034] To determine the role of lnc-ALOX12 in the IAV replication cycle, we first used immunofluorescence to detect the nuclear import of viral RNP after lnc-ALOX12 silencing in IAV-infected cells. The results showed that lnc-ALOX12 silencing did not affect the nuclear import of viral RNP within 6 hours after IAV infection ( Figure 3 , A), indicating that lnc-ALOX12 is not involved in the early stage of IAV infection. However, in the IAV replicon system, as the transfection amount of esilnc-ALOX12 increased, the IAV RNA polymerase activity decreased in a dose-dependent manner ( Figure 3 , B). Next, we used RT-qPCR to measure the levels of viral NP mRNA / vRNA / cRNA in 293T cells after lnc-ALOX12 gene silencing. The results showed that as the transfection amount of esilnc-ALOX12 increased, the levels of all three NP transcripts (vRNA / mRNA / cRNA) gradually decreased ( Figure 3 , C). This indicates that lnc-ALOX12 plays a positive regulatory role in the transcription and replication of IAV.

[0035] Example 4 lnc-ALOX12 silencing inhibits viral PB2 nuclear import

[0036] To further explore the mechanism by which lnc-ALOX12 silencing leads to a decrease in viral polymerase activity, we repeated the polymerase activity experiment. Western results showed that lnc-ALOX12 silencing significantly reduced the level of PB2 protein, while having little effect on the levels of PA and PB1 proteins ( Figure 4 , A). The nuclear-cytoplasmic fractionation experiment showed that compared with esiEGFP control cells ( Figure 4 , lane 6 in B), the level of PB2 in the nucleus of lnc-ALOX12-silenced cells ( Figure 4 , lane 8 in B) was significantly reduced, and treatment with the proteasome inhibitor MG132 could not significantly alleviate the effect of lnc-ALOX12 silencing on PB2 nuclear import ( Figure 4 , B), indicating that lnc-ALOX12 silencing inhibits the nuclear import of PB2.

[0037] PB2 depends on the classical importin protein (importin) pathway, that is, nuclear import is achieved through direct interaction with importin-α / β1. Therefore, we attempted to determine whether lnc-ALOX12 silencing would affect the interaction between PB2 and importin proteins. Lnc-ALOX12-silenced or esiEGFP control cells were co-transfected with viral RNP subunit expression plasmids (PA, PB1, PB2, and NP) and the viral minigenome Po1I-luc. Immunoprecipitation was performed with anti-importin-α1 or anti-importin-β antibody, and then the level of PB2 in the precipitate was determined by Western blotting. The results showed that the binding of PB2 to importin-α1 and importin-β was significantly weakened after lnc-ALOX12 silencing ( Figure 4 , C). Proximity ligation assay (PLA) is a powerful tool for highly specific in situ detection of intermolecular interactions. The red fluorescent dots in the PLA images represent the binding of PB2 and importin. The fluorescence signals of 30 cells were counted ( Figure 4 , D), and lnc-ALOX12 silencing could significantly reduce their binding, which was consistent with the above co-immunoprecipitation results. In summary, these results indicate that lnc-ALOX12 silencing inhibits the interaction between PB2 and importin proteins and inhibits the nuclear import of PB2.

[0038] Example 5 lnc-ALOX12 is involved in PB2 mutant-mediated host adaptation

[0039] The interaction between PB2 and importin proteins plays an important role in the interspecies transmission of influenza viruses. Adaptive mutations in the viral polymerase, especially the PB2 subunit E627K and D701N, have been shown to be important host range determinants. Therefore, we further explored whether lnc-ALOX12 might be involved in PB2 mutant-mediated host adaptation. The WSN (H1N1) virus has an adaptive mutation at amino acid position 627 of PB2 (PB2 627K), but retains the avian characteristic at amino acid position 701 of PB2 (PB2 701D). Based on this PB2 (WSN-PB2), we constructed two single mutants of the PB2 subunit, K627E and D701N, named avian-PB2 and mammal-PB2, respectively. As expected, the polymerase activity of the one containing mammal-PB2 increased by about 2.5-fold, while the polymerase activity of avian-PB2 decreased significantly ( Figure 5, A), which is consistent with previous studies. Next, we used RIP technology to detect the binding ability between lnc-ALOX12 and PB2 and its mutants. The results showed that lnc-ALOX12 could bind to the wild-type PB2 protein of the WSN virus strain (WSN-PB2) and the D701N mutant PB2 protein (mammal-PB2), and hardly bind to avian-PB2 ( Figure 5 , B). The same polymerase activity assay as above was performed in 293T cells transfected with si-ALOX12. The data showed that silencing of lnc-ALOX12 significantly affected the polymerase activities containing WSN-PB2 and mammal-PB2, but did not affect the polymerase activity of avian-PB2 ( Figure 5 , C). These results suggest a potential role of lnc-ALOX12 in the adaptation of avian influenza virus to mammalian hosts.

[0040] To further verify that lnc-ALOX12 is involved in the host adaptation process mediated by PB2 mutants, we first predicted the homologous lnc-ALOX12 in the avian genome using UCSC liftOver and AUGUSTUS tools (galGal6_dnarange=chr6:18475151-18481635) and obtained the sequence of chicken lnc-ALOX12 (chlnc-ALOX12). Knockdown of chlnc-ALOX12 in chicken DF-1 cells significantly reduced the polymerase activity of avian-PB2, but had relatively limited effects on the vRNP activities of mammalian characteristic WSN-PB2 and mammal-PB2 ( Figure 5 , D), indicating that chlnc-ALOX12 is more inclined to support the corresponding avian virus polymerase in chicken DF-1 cells. Similarly, overexpression of chlnc-ALOX12 significantly enhanced the polymerase activity of avian-PB2 in human 293T cells ( Figure 5 , E).

[0041] We further evaluated the effects of overexpression and knockdown of chlnc-ALOX12 on the interaction between importin-α and WSN-PB2 or avian-PB2 by Co-IP assays in 293T and DF-1 cells. The results showed that overexpression of chlnc-ALOX12 in 293T cells did not affect the binding of mammalian characteristic WSN-PB2 to importin-α1, but could enhance the binding of avian-PB2 to importin-α1 ( Figure 5, F). Similarly, in chicken DF-1 cells, knocking out chlnc-ALOX12 decreased the level of avian-PB2 in the co-precipitation with importin-α3, but had no effect on the level of WSN-PB2 ( Figure 5 , G), which indicates that the effect of lnc-ALOX12 on the PB2 / importin interaction is species-specific.

[0042] In summary, the present invention for the first time discovers that lnc-ALOX12 promotes the binding of PB2 to the host importin in a species-specific manner, thereby ensuring the effective nuclear import of PB2 and viral RNA synthesis.

[0043] Although the present invention has been described in detail with general descriptions and specific embodiments above, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

Claims

1. Application of substances inhibiting lnc-ALOX12 in the preparation of influenza virus inhibitors; The lnc-ALOX12 is a long non-coding RNA from humans, and the sequences of its two transcripts are shown in SEQ ID NO: 1 and SEQ ID NO: 2; The influenza virus is influenza A virus; The substance that inhibits lnc-ALOX12 is esilnc-ALOX12, and its target sequence acting on lnc-ALOX12 is shown in SEQ ID NO: 3.

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