Method for determining the viral or bacterial nature of an infection

Abstract

The present invention relates to in vitro or ex vivo methods and kits for determining the viral or bacterial nature of an infection on the basis of a biological sample of a patient by identifying the change in the level of expression of a plurality of biomarkers. In particular, the method comprises the steps of (a) measuring the expression of at least one viral target gene and of at least one bacterial target gene chosen from among OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2; (b) comparing the expressions measured in step (a) with reference expression values for these target genes; and (c) on the basis of the results of the comparison, concluding whether the infection is viral or bacterial in nature .

Description

[0001] METHOD FOR DETERMINING THE VIRAL OR BACTERIAL NATURE OF AN INFECTION

[0002] TECHNICAL FIELD

[0003] The present invention relates to the technical field of in vitro diagnostic methods and kits. In particular, the invention relates to methods and kits for determining, from a biological sample of a subject, the nature of an infection, namely viral or bacterial, by identifying the variation in the level of expression of several biomarkers.

[0004] PRIOR TECHNIQUE

[0005] Viruses and bacteria interact with different recognition receptors on the surface of leukocytes present in the circulating blood. This interaction triggers specific transcriptional events in the host that regulate the immune response (Takeuchi et al. 2010). Therefore, differential activation of host transcriptional programs generates unique transcriptomic signatures that can help distinguish viral from bacterial causes.

[0006] In this context, analysis of host transcriptomic profiling can provide an indirect approach to detecting the nature of an infection, complementing direct approaches, such as culture or nucleic acid amplification (Ramilo et al. 2009). This is also of particular interest because viral infections frequently cause fever without apparent source, especially in young children.

[0007] Furthermore, considering the common practice in hospitals of routinely administering antibiotics to febrile patients as a preventative measure until culture test results are available, unfortunately, many viral infections are wrongly treated with antimicrobial drugs.

[0008] Furthermore, it has been shown that excessive administration of antibiotics leads to an increase in bacterial resistance, not only at the individual level but also at a more global level. Therefore, the misuse and overuse of available antibiotics actively contribute to the development of antimicrobial resistance (Fauci et al. 2014). Furthermore, due to the difficulties in distinguishing between viral, bacterial, or non-infectious etiologies, a number of patients are inappropriately treated with antibiotics at high rates.

[0009] Early distinction between patients with viral and bacterial infections could therefore allow for more precise and more accurate management of these patients, while significantly reducing unnecessary antibiotic use.

[0010] In recent years, there has been growing interest in the discovery of biomarkers capable of distinguishing viral infections from bacterial infections with similar initial clinical phenotypes based on gene expression in whole blood. For example, authors have described that the transcriptional profiles of viropositive febrile children and febrile children with acute bacterial infection differ from the profiles of viropositive and negative non-febrile children (Hu et al. 2013).

[0011] Increasing efforts are therefore being made to develop host biomarkers to distinguish viral from bacterial infections, particularly in febrile children (D. Brown et al. 2016). This interest stems not only from the need to distinguish life-threatening bacterial from viral infections, but also to avoid unnecessary prescription of empirical antibiotic therapy, regardless of the severity of the infection. As mentioned earlier, the overuse of antibiotics worldwide is accelerating antimicrobial resistance (AMR), which is recognized by the World Health Organization as one of the greatest threats to human health in the coming years.

[0012] For example, document W02018011316 describes a method for identifying a subject with a bacterial infection. In particular, the method consists in detecting in an mRNA sample the modulation of the expression of 2 to 10 genes chosen from the following gene signature: IFI44L, FAM89A, IFI27L, IFTI1, RSAD2, IFIT3, OTOF, IFIT2, EPSTI1, SERPING1, OAS1, IFI6, HLA-DRB6, HBZ, HS.386275, EIF2AK2, IFIT1L, FCER1A, C21ORF7, GYPE, GYPB, HBM, EIF1AY, LOC649143, HBD, FBX07, KCNMA1, MERTK, EBI3, UPB1, EMR1, PTPN20, TMEM119, SLPI, S100P and PI3.

[0013] Discrimination between viral and bacterial infection based on transcriptomic signatures has also been described by other authors. In particular, from an independent cohort of 623 patients, who presented with bacterial infection, viral infection, co-infection or non-infectious disease, a 45 mRNA signature was identified to discriminate between viral and bacterial infection (E L.Tsalik et al., 2021).

[0014] However, further efforts are needed to assess the accuracy and diagnostic utility of biomarkers, particularly transcriptomics, before they can be transformed into a clinically applicable test to determine the viral or bacterial origin of an infection.

[0015] Thus, although solutions exist, there is still a need to develop new transcriptomic signatures to identify the nature of an infection and thus discriminate between viral and bacterial etiologies. This is particularly important in order to improve patient care, particularly for febrile children, to reduce the inappropriate use of antibiotics and to participate in the fight against the development of antibiotic resistance.

[0016] Summary

[0017] The present invention is based on the identification of transcriptomic signatures associated with viral and bacterial infections. The method according to the invention makes it possible to identify in a subject diagnosed as having an infection, or suspected of having an infection, the nature of said infection, in order to select the most appropriate treatment. In a highly advantageous manner, the method according to the invention makes it possible to exclude the presence of a bacterial infection and to limit the inappropriate use of antibiotics.

[0018] Thus, a first aspect of the invention relates to an in vitro or ex vivo method for determining the nature of an infection in a subject by measuring, from a biological sample of said subject, the variation in the level of expression of at least one viral target gene and at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0019] The method according to the invention, from a biological sample of an infected or potentially infected subject, thus comprises the following steps: (a) measurement of the expression of at least one viral target gene and at least one bacterial target gene chosen from the bacterial target genes OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2,

[0020] (b) comparing the expressions measured in step (a) with predetermined reference expression values ​​of said target genes, and

[0021] (c) conclusion as to the viral or bacterial nature of the infection based on the comparison results.

[0022] The advantages of the method according to the invention are numerous, in particular:

[0023] (i) Accurately differentiate the viral or bacterial nature of the infection with a high level of performance, with the majority of biomarker combinations having a performance in terms of area under the curve (AUC) of at least 0.85, and sometimes even at least 0.90,

[0024] (ii) Exclude the presence of a bacterial infection, .

[0025] (iii) Rapidly identify significant variations in the level of gene expression, in particular by implementing automated systems or by means of the detection kits according to the invention,

[0026] (iv) Avoid the identification of false positives corresponding to the presence of non-pathogenic bacteria or viruses naturally present in subjects,

[0027] (v) Allow identification of the nature of the infection when the pathogen is not identifiable or when it is inaccessible. Indeed, the present method does not require direct access to the pathogen, only a biological sample from the subject is necessary.

[0028] After extensive research, it is thus to the inventors' credit that they have identified a transcriptomic signature whose expression is characteristic of the viral or bacterial nature of the infection and to use the measurement of the variation in this expression to identify the source of the infection. This is all the more remarkable since it is particularly difficult to identify effective bacterial target genes which, in particular, when combined with viral target genes, make it possible to exclude the presence of a bacterial infection.

[0029] Identifying the nature of an infection is of definite interest, in particular by enabling the clinician to be supported in providing more appropriate and personalized care, particularly to avoid the unnecessary prescription of antibiotics when the infection is viral in nature or when the presence of a bacterial infection is excluded.

[0030] Preferably, the measuring step (a) comprises or consists of measuring at least one viral target gene selected from the host viral genes involved in the pro-inflammatory cytokine pathway, in the interferon pathway, in the Toll-like receptor (TLR) signaling pathway, in the RIG-I-like receptor (RIG-I-like receptor) signaling pathway and in the Major Histocompatibility Complex (MHC) class II-mediated antigen presentation pathway, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0031] Preferably, the measuring step (a) comprises or consists of measuring at least one viral target gene selected from among the host viral genes involved in the interferon pathway and MHC class II-mediated antigen presentation, and at least one bacterial target gene selected from among OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0032] Preferably, the measuring step (a) comprises or consists of measuring at least one viral target gene selected from the viral genes of the host involved in the interferon pathway, and in particular, said genes are selected from the viral target genes IFI27, IFN-a, IFN-P, IFN-e, IFN-K, IFN-CÛ, IFN-y, IFNL1, IFNL2, IFNL3, ADAR1, IFIT1, IFIT2, IFIT3, IFIT5, IFI44L, ISG15, ISG20, MDA5, OAS1, OAS2, OAS3, OASL, PARP12, PKR, RIG-I, RNaseL, TRIM25, ZAP, ZCCHC3, ZNFX1, RBBP6, SHFL, TRIM22, TRIM25, TRIM32, TRIM69, Viperin, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6 and combinations thereof, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0033] Preferably, the measuring step (a) comprises or consists of the measurement of at least one viral target gene selected from RSAD2, IFI27, OAS1, IFIT1, IFI44L, SIGLEC1, ISG15 and HERC6, and of at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0034] Preferably, the measuring step (a) comprises or consists of the measurement of at least one viral target gene chosen from RSAD2, IFI27, OAS1, IFIT1, IFI44L, SIGLEC1, ISG15 and HERC6, and the bacterial target gene FAM20A and optionally at least one other bacterial target gene chosen from OLAH, IL1R2, MMP8, RETN and SLC1A2.

[0035] Preferably, the measuring step (a) comprises or consists of the measurement of at least one viral target gene selected from ISG15 and OAS1, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0036] Preferably, the measuring step (a) comprises or consists of measuring at least one viral target gene selected from SIGLEC1, ISG15 and HERC6 and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. More preferably, the measuring step (a) comprises or consists of measuring the viral target genes SIGLEC1, ISG15 and HERC6, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0037] Preferably, the measuring step (a) comprises or consists of the measurement of at least one viral target gene selected from RSAD2, IFI27, OAS1, IFIT1, IFI44L, SIGLEC1, ISG15 and HERC6, and of at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0038] Preferably, the measuring step (a) comprises or consists of the measurement of at least one viral target gene selected from SIGLEC1, ISG15 and HERC6, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0039] Preferably, step (a) comprises or consists of the measurement of at least one viral target gene selected from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2,

[0040] Preferably, step (a) comprises measuring the expression of the viral target gene IFI27 and the bacterial target gene OLAH, and more preferably, also measuring the expression of the bacterial target gene FAM20A.

[0041] Preferably, the measuring step (a) comprises or consists of measuring the expression of two viral target genes selected from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L and two bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably selected from OLAH, FAM20A, IL1R2 and MMP8.

[0042] Preferably, the measuring step (a) comprises or consists of measuring the expression of two to five viral target genes selected from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L and three or four bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably selected from OLAH, FAM20A, IL1R2 and MMP8.

[0043] Preferably, the measuring step (a) comprises or consists of measuring the expression of the viral target gene IFI27, and optionally of at least one other viral gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L, and of at least two bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH, FAM20A, IL1R2 and MMP8.

[0044] Preferably, step (a) comprises or consists of measuring at least one viral target gene selected from SIGLEC1, ISG15 and HERC6, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from IL1R2, OLAH and FAM20A.

[0045] Preferably, step (a) comprises or consists of measuring at least one viral target gene selected from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, the bacterial target gene OLAH, and at least one other bacterial target gene selected from FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from FAM20A, IL1R2 and MMP8.

[0046] Preferably, step (a) comprises or consists of measuring at least one viral target gene selected from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, the bacterial target gene FAM20 A, and at least one other bacterial target gene selected from OLAH, IL1R2, MMP8, RETN and SLC1A2, preferably from OLAH, IL1R2 and MMP8.

[0047] Preferably, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, another viral target gene selected from HERC6, SIGLEC1, IFI44L and ISG15, the bacterial target gene FAM20A and another bacterial target gene selected from OLAH and IL1R2.

[0048] Preferably, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, two other viral target genes selected from SIGLEC1, HERC6, OAS1 and IFIT1, the bacterial target gene FAM20A and another bacterial target gene selected from OLAH, IL1R2 and MMP8.

[0049] Preferably, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, of another viral target gene selected from IFIT1, HERC6, ISG15 and ISG15, of the bacterial target genes FAM20A and MMP8, and of another bacterial target gene selected from OLAH and IL1R2.

[0050] Preferably, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, and two other viral target genes selected from IFIT1, OAS1, HERC6 and ISG15, the bacterial target genes FAM20A and MMP8, and another bacterial target gene selected from OLAH and IL1R2.

[0051] Preferably, step (a) consists of measuring a combination of viral and bacterial target genes chosen from the combinations of target genes listed in Tables 6 to 12 and which have an AUC of the model for determining the viral or bacterial nature of the infection of at least 0.90. Preferably, in the method according to the invention, the reference expression value of the target genes corresponds to the respective expression of said target genes in a reference biological sample obtained from a subject having a bacterial infection. Thus, it may be concluded that there is an infection of a viral nature when the comparison of the level of expression of the target genes at the level of the mRNA transcripts with respect to the respective reference values ​​highlights at least one variation in expression chosen from:

[0052] - overexpression of SIGLEC1,

[0053] - overexpression of ISG15,

[0054] - overexpression of HERC6,

[0055] - overexpression of RSAD2,

[0056] - overexpression of IFI27,

[0057] - overexpression of OAS1,

[0058] - overexpression of IFIT1, and

[0059] - an overexpression of IFI44L, and at least one other expression variation chosen from:

[0060] - underexpression of SLC1A2,

[0061] - an underexpression of IL1R2,

[0062] - underexpression of FAM20A,

[0063] - a sub-expression of OLAH,

[0064] - an underexpression of RETN, and

[0065] - an underexpression of MMP8.

[0066] More preferably, in the method according to the invention, the reference expression value of said target genes corresponds to the respective expression of said target genes in a reference biological sample obtained from a subject having a viral infection. Thus, it can be concluded that there is an infection of a bacterial nature when the results of the comparison of the expression of the target genes highlight at least two variations chosen from the following variations:

[0067] - an underexpression of SIGLEC1,

[0068] - an underexpression of ISG15,

[0069] - underexpression of HERC6,

[0070] - an underexpression of RSAD2,

[0071] - a sub-expression of IFI27,

[0072] - an underexpression of OAS1, - an underexpression of IFIT1, and

[0073] - a sub-expression of IFI44L, and at least one other expression variation chosen from:

[0074] - overexpression of SLC1A2,

[0075] - overexpression of IL1R2,

[0076] - overexpression of FAM20A,

[0077] - an overexpression of OLAH,

[0078] - overexpression of RETN, and

[0079] - overexpression of MMP8.

[0080] Preferably, the method according to the invention further comprises a step (a') of measuring the expression of at least one additional target gene chosen from PI3, EBI3, ADGRE1 and S100P, a step (b') of comparing the expressions measured in step (a') with reference expression values ​​of said additional target genes and a step (c'j) of concluding as to the viral or bacterial nature of the infection on the basis of the comparative results.

[0081] Preferably, in the method according to the invention, the measurement of the expression of the target genes is carried out at the mRNA level.

[0082] Preferably, in the method according to the invention, the measurement of the variation in expression is carried out by amplification via RT-PCR, preferably quantitative RT-PCR, or nested PCR.

[0083] Preferably, in the method according to the invention, the expression is normalized relative to the expression of one or more housekeeping genes chosen from DECRI, HPRT1, PPIB, GAPDH, and ACTB.

[0084] Preferably, in the method according to the invention the subject is a child, preferably a child under 4 years of age, and more preferably, a child under 4 years of age.

[0085] Preferably, in the method according to the invention, the biological sample is a blood sample, preferably a whole blood sample.

[0086] The invention also relates to a kit for in vitro or ex vivo measurement of the expression of at least one viral target gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1, IFI44L, and at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, said kit comprising reagents specific for the expression products of said target genes, said reagents preferably being primers or probes. The kit is particularly suitable for implementing the method according to the invention and thus makes it possible to determine the viral or bacterial nature of an infection from a biological sample of a subject.

[0087] BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents the box plots of the expression of the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8 obtained from the raw RT-PCR values ​​normalized with the housekeeping genes DECRI, HPRT1 and PPIB; A: Bacterial infection (n=68); B: Viral infection (n=123).

[0088] Figure 2 represents the box plots of the expression of the target genes RSAD2, IFI27, OAS1, IFIT1 and IFI44L obtained from the RT-PCR bmtes values ​​normalized with the housekeeping genes DECRI, HPRT1 and PPIB; A: Bacterial infection (n=68); B: Viral infection (n=123).

[0089] DETAILED DESCRIPTION

[0090] The transcriptome is the set of RNAs resulting from the transcription of the genome. Transcriptomic analysis can characterize the entire or partial transcriptome of a particular tissue or cell type, or compare transcriptomes between different experimental or clinical conditions. Pathogens such as viruses and bacteria interact in the host with different recognition receptors on the surface of leukocytes present in the circulating blood. As mentioned previously, this interaction leads to specific transcriptional events that regulate the immune response, thus generating specific transcriptomic signatures.

[0091] Transcriptomic signatures can therefore be decision-making tools based on an analysis of previously selected gene transcripts.

[0092] A first subject of the invention relates to an in vitro or ex vivo method for determining the viral or bacterial nature of an infection in a subject. More particularly, the inventors have identified that the demonstration, from a biological sample of an infected or potentially infected subject, of the variation in the level of expression of several target genes made it possible to characterize the viral or bacterial nature of the infection. In other words, the method according to the invention makes it possible to exclude the presence of a bacterial infection.

[0093] Thus, the method according to the invention comprises the following steps:

[0094] (a) measurement, from the biological sample of an infected subject, of the expression of at least one viral target gene and at least one bacterial target gene chosen from the bacterial target genes OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2,

[0095] (b) comparing the expressions measured in step (a) with predetermined reference expression values ​​of said target genes, and

[0096] (c) conclusion as to the viral or bacterial nature of the infection of said subject on the basis of the comparison results.

[0097] The term "viral target gene" refers to a host gene whose expression is deregulated in the presence of a viral infection, i.e., a gene whose expression is significantly increased or decreased in the presence of said infection. The term "bacterial target gene" refers to a host gene whose expression is deregulated in the presence of a bacterial infection, i.e., a gene whose expression is significantly increased or decreased in the presence of said infection.

[0098] For the purposes of this description, the expression "target gene" refers indifferently to a viral target gene or a bacterial target gene unless the context makes it possible to clearly identify whether it is a viral target gene or a bacterial target gene.

[0099] The terms "biomarker" or "marker" refer to an objectively measurable biological characteristic that represents an indicator of normal or pathological biological processes following the presence of an infection. Thus, for the purposes of the present invention, biomarkers are viral target genes and bacterial target genes, and in particular the transcripts of said target genes.

[0100] For the entirety of this description, when reference is made to the measurement of the expression of "at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2", this includes the possibility of measuring the expression of several target genes, thus de facto encompassing all possible combinations of 2 to 6 bacterial target genes without it being necessary to give an exhaustive list. This applies to all lists of target genes introduced in this description by the expression "at least" and therefore also concerns the measurement of the expression of viral target genes.

[0101] The expression "infected subject" refers to a subject having an infection, in other words, a subject having been diagnosed as having an infection. The diagnosis of the presence of the infection can be made by any method known to the person skilled in the art allowing such a conclusion to be made. The diagnosis can thus be made by a molecular method, such as for example a procalcitonin (PCT) protein assay, or directly by the clinician on the basis of the symptom(s) or clinical sign(s) of the subject.

[0102] The symptoms or clinical signs associated with the presence of an infection are also well known to the person skilled in the art, and examples include headaches, pain in a specific part of the body (the abdomen for example), fever (>38°C) with or without chills, a body temperature below 35.5°C, a respiratory symptom chosen from the group comprising cough, expectoration, dyspnea, tachypnea and pleuritic pain; a finding on auscultation, nausea with or without vomiting, systolic blood pressure above 90 mmHg, heart rate above 120 beats / min, a symptom of infection of an organ or organ system chosen from the group consisting of respiratory tract infections, digestive tract infections, vaginal infections, meningitis, septicemia, erysipelas, peritonitis, cholangitis, cholecystitis and osteomyelitis.

[0103] Therefore, the method according to the invention makes it possible to identify the nature of the infection of said subject.

[0104] The expression "nature of the infection" refers only to the etiology of said infection, namely a viral infection or a bacterial infection. The method according to the invention thus makes it possible to distinguish a viral infection from a bacterial infection, or vice versa. In other words, the method according to the invention makes it possible to exclude the presence of a bacterial infection. For the purposes of the present description, the term "subject" designates a human being and preferably, the subject is a patient. By definition, the patient is a person who has come into contact with a healthcare professional, in particular a doctor, a medical facility or a healthcare establishment.

[0105] The target genes involved in the method according to the invention are well known to those skilled in the art, but it is to the credit of the inventors to have identified that transcriptomic signatures based on the variation in expression of said genes could make it possible to effectively determine the viral or bacterial nature of an infection.

[0106] Indeed, the person skilled in the art is able to identify the viral target genes, for the implementation of the method according to the invention. The same applies to the chromosomal positions of said target genes which are accessible in public databases, such as for example in the Ensembl database (GRCh38 / hg38 assembly).

[0107] Thus, any viral target gene, the expression of which is significantly increased or decreased in the presence of an infection, can be used in the method according to the invention. Such genes are known to those skilled in the art.

[0108] Therefore, viral target genes can be selected from genes of the interferon pathway, the pro-inflammatory cytokine pathway, the Toll-like receptor (TLR) signaling pathway, the RIG-I-like receptor (RIG-I-like receptor) signaling pathway, or the MHC class II-mediated antigen presentation pathway.

[0109] The viral target genes of the interferon pathway, in particular the genes stimulated by interferons, known as ISG genes, are well known to those skilled in the art (Schneider et al, 2014; Yang et al. 2020). Examples of such genes include IFN-a, IFN-P, IFN-e, IFN-K, IFN-CÛ, IFN-y, IFNL1, IFNL2, IFNL3, ADAR1, IFIT1, IFIT2, IFIT3, IFIT5, IFI27, IFI44L, ISG15, ISG20, MDA5, OAS1, OAS2, OAS3, OASL, PARP12, PKR, RIG-I, RNaseL, RSAD2, RBBP6, SIGLEC1, SHFL, TRIM22, TRIM25, TRIM32, TRIM69, Viperin, ZAP, ZCCHC3, and ZNFXl.

[0110] Viral target genes of the pro-inflammatory cytokine pathway are also well known to those skilled in the art (Mogensen et al. 2001). Examples of such genes include TNFα, IL-ip, IL-6, IL-IRα, IL-8, GM-CSF, MIP-lo, MIP-ip, IL-10, IL-la, TGF-β, TGF-βα, IL-2, IL-4, IL-13, IL-15, IL-3, IL-5, IP10, and SCM-1.

[0111] Thus, according to a particular embodiment, the measurement step (a) comprises or consists of the measurement of at least one viral target gene chosen from the viral genes of the host involved in the proinflammatory cytokine pathway, and in particular chosen from the viral target genes TNFa, IL-ip, IL-6, IL-IRa, IL-8, GM-CSF, MIP-la, MIP-ip, IL-10, IL-la, TGF-P, TGF-pi, IL-2, IL-4, IL-13, IL-15, IL-3, IL-5, IP10, SCM-1 and combinations thereof, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0112] The viral target genes of the Toll-like receptor pathway are also well known to those skilled in the art (Kawasaki et al., 2014) and include, in particular, native TLR genes, TLR co-receptor genes, TLR regulator genes, TLR signaling inhibitors, TLR adaptor genes, and TLR signaling genes.

[0113] Examples of native TLR genes include TLR3, TLR7, TLR8, and TLR9.

[0114] Examples of TLR co-receptor genes include CD14, LBP, MD1, and MD2.

[0115] Examples of TLR regulatory genes include CD300LF, GRP94, PRAT4A, PRAT4B, and UNC93Bl.

[0116] As an example of genes inhibiting TLR signaling, mention will be made in particular of the genes ATF3, AXL, BAMBI, BCL3, BPI, CENTB1, DAK, FLII, HSP10, IRAKM(IRAK3), LGP2(DHX58), MSK1, MSK2, NLRP12(NALP12), NFKBIA, NFKBIB, NFKBIE, PECAM1, PIN1, PPP3CA, PPP3CB, PPP3R1, PTPN6, RNF125, RP105, SHIP1, SIGIRR, SIKE, TNFAIP3, TNIP1, TNIP2, TNIP3, TOLLIP, TRAFD1, TRIAD3, TYRO3 and ZCCHCl l.

[0117] Examples of TLR adaptor genes include MyD88, RAC1, SARM1, TANK, TIRAP, TRAM(TICAM2) and TRIF(TICAMl).

[0118] <h2 style=";text-align:left;direction:ltr">An example of TLR signaling genes, we mention notably the genes AAMP, ACT1(TRAF3IP2), AGER, AKT1, BECN1, BTK, CARD6, CARD11, DDX3X, FADD, IKKa, IKK(3, IKKe, IPS1, IRAKI, IRAK4, IRF1, IRF3, IRF5, IRF7, IRF8, IRF9, ITCH, LRRC59, LRRFIP2, MAP2K2, MAP3K7(TAK1), MAPK1, MDA5(IFIH1), NAIP5, NAP1, NEMO, NIBP, OTUD5, PKR, PRKRA, RIG-1, RIPK1, RIPK2, RIPK3, STAP2, SUGT1, SYK, TAB1, TAB2, TAB3, TBK1, TBKBP1, TIFA, TRADD, TRAF3, TRAF6, TRIL and WDFY1.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0119] Thus, according to a particular embodiment, the measurement step (a) comprises or consists of the measurement of at least one viral target gene chosen from the viral genes of the host involved in the signaling pathway of the TLR receptors, and in particular chosen from TLR3, TLR7, TLR8, TLR9, CD14, LBP, MD1, MD2, CD300LF, GRP94, PRAT4A, PRAT4B, UNC93B1 ATF3, AXL, BAMBI, BCL3, BPI, CENTB1, DAK, FLII, HSP10, IRAKM(IRAK3), LGP2(DHX58), MSK1, MSK2, NLRP12(NALP12), NFKBIA, NFKBIB, NFKBIE, PECAM1, PIN1, PPP3CA, PPP3CB, PPP3R1, PTPN6, RNF125, RP105, SHIP1, SIGIRR, SIKE, TNFAIP3, TNIP1, TNIP2, TNIP3, TOLLIP, TRAFD1, TRIAD3, TYRO3, ZCCHC11, MyD88, RAC1, SARM1, TANK, TIRAP, TRAM(TICAM2), TRIF(TICAMl), AAMP, ACT1(TRAF3IP2), AGER, AKT1, BECN1, BTK, CARD6, CARD11, DDX3X, FADD, IKKa, IKK(3, IKKe, IPS1, IRAKI, IRAK4, IRF1, IRF3, IRF5, IRF7, IRF8, IRF9, ITCH, LRRC59, LRRFIP2, MAP2K2, MAP3K7(TAK1), MAPK1, MDA5(IFIH1), NAIP5, NAP1, NEMO, NIBP, OTUD5, PKR, PRKRA, RIG-1, RIPK1, RIPK2, RIPK3, STAP2, SUGT1,SYK, TAB1, TAB2, TAB3, TBK1, TBKBP1, TIFA, TRADD, TRAF3, TRAF6, TRIL, WDFY1 and combinations thereof, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.,

[0120] Viral target genes of the RIG-I-like receptor signaling pathway are also known to those skilled in the art. Examples include LGP2(DHX58), MDA5(IFIH1), RIG-I(DDX58), TRAFD1, CYLD, DAK, DDX60, MFN2, MUL1, OTUD5, PIN1, RNF125, SIKE, TNFAIP3, IPS1, IPS1-HA, PARP13, STING, TOMM70A, TRIM13, TRIM26, TRIM32, and ZDHHC1. Thus, according to a particular embodiment, the measurement step (a) comprises or consists of the measurement of at least one viral target gene chosen from the viral genes of the host involved in the signaling pathway of the RLR receptors, and in particular, said genes are chosen from the viral target genes LGP2(DHX58), MDA5(IFIH1), RIG-I(DDX58), TRAFD1, CYLD, DAK, DDX60, MFN2, MUL1, OTUD5, PIN1, RNF125, SIKE, TNFAIP3, IPS1, IPS1-HA, PARP13, STING, TOMM70A, TRIM13, TRIM26, TRIM32, ZDHHC1 and combinations thereof, and at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0121] Finally, the viral target genes of the MHC class II-mediated antigen presentation pathway are also well known to those skilled in the art. For example, the target genes of the ubiquitin ligase family, including HERC1, HERC2, HERC3, HERC4, HERC5, and HERC6 (Hochrainer et al., 2005), may be cited.

[0122] Thus, according to a particular embodiment, the viral target genes whose expression is measured in step (a) are chosen from the viral target genes of the pro-inflammatory cytokine pathway, the interferon pathway, the Toll-like receptor (TLR) signaling pathway, the RIG-I-like receptor (RIG-I-like receptor) (RLR) signaling pathway, and the MHC class II-mediated antigen presentation pathway.

[0123] According to a particular embodiment, the viral target genes whose expression is measured in step (a) are chosen from TNFa, IL-ip, IL-6, IL-IRa, IL-8, GM-CSF, MIP-la, MIP-ip, IL-10, IL-la, TGF-P, TGF-pi, IL-2, IL-4, IL-13, IL-15, IL-3, IL-5, IP10, SCM-1, IFN-a, IFN-P, IFN-e, IFN-K, IFN-CÛ, IFN-y, IFNL1, IFNL2, IFNL3, ADAR1, IFIT1, IFIT2, IFIT3, IFIT5, IFI27, IFI44L, ISG15, ISG20, MDA5, OAS1, OAS2, OAS3, OASL, PARP12, PKR, RIG-I, RNaseL, ZAP, ZCCHC3, ZNFX1, RBBP6, SHFL, TRIM22, TRIM25, TRIM32, TRIM69, Viperin, TLR3, TLR7, TLR8, TLR9, CD14, LBP, MD1, MD2, CD300LF, GRP94, PRAT4A, PRAT4B, UNC93B1 ATF3, AXL, BAMBI, BCL3, BPI, CENTB1, DAK, FLII, HSP10, IRAKM(IRAK3), LGP2(DHX58), MSK1, MSK2, NLRP12(NALP12), NFKBIA, NFKBIB, NFKBIE, PECAM1, PIN1, PPP3CA, PPP3CB, PPP3R1, PTPN6, RNF125, RP105, SHIP1, SIGIRR, SIKE, TNFAIP3, TNIP1, TNIP2, TNIP3, TOLLIP, TRAFD1, TRIAD3, TYRO3, ZCCHC11, MyD88, RAC1, SARM1, TANK, TIRAP, TRAM(TICAM2), TRIF(TICAMl), AAMP, ACT1(TRAF3IP2), AGER, AKT1, BECN1,BTK, CARD6, CARD11, DDX3X, F ADD, IKKa, IKKp, IKKe, IPS1, IRAKI, IRAK4, IRF1, IRF3, IRF5, IRF7, IRF8, IRF9, ITCH, LRRC59, LRRFIP2, MAP2K2, MAP3K7(TAK1), MAPK1, MDA5(IFIH1), NAIP5, NAP1, NEMO, NIBP, OTUD5, PKR, PRKRA, RIG-1, RIPK1, RIPK2, RIPK3, STAP2, SUGT1, SYK, TAB1, TAB2, TAB3, TBK1, TBKBP1, TIFA, TRADD, TRAF3, TRAF6, TRIL, WDFY1, LGP2(DHX58), MDA5(IFIH1), RIG-I(DDX58), TRAFD1, CYLD, DAK, DDX60, MFN2, MUL1, OTUD5, PIN1, RNF125, SIKE, TNFAIP3, IPS1, IPS1-HA, PARP13, STING, TOMM70A, TRIM13, TRIM26, TRIM32, ZDHHC1, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6 and combinations thereof.,

[0124] According to a preferred embodiment, the viral target genes whose expression is measured in step (a) are chosen from the viral target genes of the interferon pathway and of the MHC class II-mediated antigen presentation pathway.

[0125] According to another preferred embodiment, the measuring step (a) comprises or consists of measuring at least one viral target gene selected from IFN-a, IFN-P, IFN-e, IFN-K, IFN-CÛ, IFN-y, IFNL1, IFNL2, IFNL3, ADAR1, IFIT1, IFIT2, IFIT3, IFIT5, IFI27, IFI44L, ISG15, ISG20, MDA5, OAS1, OAS2, OAS3, OASL, PARP12, PKR, RIG-I, RNaseL, RSAD2, RBBP6, SIGLEC1, SHFL, TRIM22, TRIM25, TRIM32, TRIM69, Viperin, ZAP, ZCCHC3, ZNFX1, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6 and combinations thereof, and of at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0126] 5 According to another preferred embodiment, the measuring step (a) comprises or consists of the measurement of at least one viral target gene selected from IFI27, IFN-y, IFIT1, IFIT2, IFI44L, ISG15, OAS1, OAS2, OAS3, RSAD2, TRIM25, SIGLEC1, TRIM22, TRIM32, HERC5, HERC6 and combinations thereof, and of at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0127] According to another particularly preferred embodiment, the measurement step (a) comprises or consists of the measurement of at least one viral target gene chosen from SIGLEC1, RSAD2, IFI27, OAS1, IFIT1, IFI44L, ISG15 and

[0128] HERC6, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0129] The chromosomal positions of the target genes according to this preferred embodiment are given in particular in Table 1 below:

[0130] [Table 1]

[0131] The SIGLEC1 gene encodes a member of the immunoglobulin superfamily. The encoded protein is a lectin-like adhesion molecule that binds glycoconjugated ligands on cell surfaces in a sialic acid-dependent manner. It is a type I transmembrane protein expressed only by a subpopulation of macrophages and is involved in mediating cell-cell interactions.

[0132] The ISG15 gene encodes a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been attributed to the encoded protein, including chemotactic activity toward neutrophils, directing conjugated target proteins to intermediate filaments, intercellular signaling, and antiviral activity during viral infections.

[0133] The HERC6 gene belongs to the HERC family of ubiquitin ligases, all of which contain at least a 350-amino acid HECT domain that catalyzes the formation of a thioester with ubiquitin before transferring it to a substrate.

[0134] The SLC1 A2 gene encodes a member of a family of solute carrier proteins. This membrane-bound protein is the primary transporter that removes glutamate, an excitatory neurotransmitter, from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage due to excessive activation of glutamate receptors.

[0135] The IL1R2 gene encodes a cytokine receptor protein that belongs to the interleukin 1 receptor family. This protein binds interleukin alpha (IL1(A), interleukin beta (IL1B), and interleukin 1 receptor type I (IL1R1 / IL1R(A), and acts as a decoy receptor that inhibits the activity of its ligands. Interleukin 4 (IL4) is thought to antagonize the activity of interleukin 1 by inducing the expression and release of this cytokine. This gene and three other genes form a cytokine receptor gene cluster on chromosome 2ql2. Alternative splicing results in multiple transcript variants and isoforms of membrane and soluble proteins.

[0136] The FAM20A gene encodes a presumably secreted protein that may play a role in hematopoiesis. A mutation at this locus has been associated with amelogenesis imperfecta and gingival hyperplasia syndrome.

[0137] The OLAH gene enables dodecanoyl-[acyl carrier-protein] hydrolase activity; myristoyl-[acyl carrier-protein] hydrolase activity; and palmitoyl-[acyl carrier-protein] hydrolase activity. It is involved in the biosynthesis of medium-chain fatty acids.

[0138] The RETN gene encodes a protein with an antimicrobial role in the skin via antibacterial activity against Gram-positive and Gram-negative bacteria.

[0139] The MMP8 gene encodes a member of the matrix metalloproteinase (MMP) protein family. These proteins are involved in the degradation of the extracellular matrix during embryonic development, reproduction, and tissue remodeling, as well as in pathological processes, such as arthritis and metastasis. Proteolysis at different sites on this protein results in several active forms of the enzyme with distinct N-termini. This protein functions in the degradation of type I, II, and III collagens.

[0140] The RASAD2 gene encodes an interferon-inducible antiviral protein that belongs to the S-adenosyl-L-methionine (SAM) enzyme superfamily, which plays a role in the cellular antiviral response and innate immune signaling. Antiviral effects result from, among other things, inhibition of viral RNA replication, interference with the secretory pathway, binding to viral proteins, and deregulation of cellular lipid metabolism.

[0141] The IFI27 gene is notably involved in the metabolic process of cellular proteins, the defense response to other organisms and the extrinsic apoptotic signaling pathway. This gene also acts upstream or in the negative regulation of transcription by RNA polymerase II and the regulation of protein export from the nucleus.

[0142] The OAS1 gene encodes a protein that synthesizes 2',5'-oligoadenylates (2-5 As) and plays a key role in the innate cellular antiviral response.

[0143] The IFIT1 gene encodes a protein containing tetratricopeptide repeats originally identified as being induced by interferon treatment. The encoded protein can inhibit viral replication and translation initiation.

[0144] The IFI44L gene is associated with GTP binding activity and involved in the defense response to viruses.

[0145] According to the present description, the identification or measurement of the level of gene expression consists of highlighting a variation in the expression at the transcriptomic level of said genes, said variation being highlighted in relation to a reference expression of said genes. For this reason, we will speak in particular of a transcriptomic signature.

[0146] The transcripts of the various target genes useful for implementing the method according to the present description are also known to those skilled in the art and their sequences are made available in the NCBI or Ensembl databases.

[0147] Examples of transcripts are shown in Table 2 below for some preferred viral and bacterial target genes:

[0148] [Table 2]

[0149] According to a particular embodiment, the measurement of the expression of the viral and bacterial target genes is carried out at the level of the mRNA transcripts, and preferably at the level of the transcripts chosen from the transcripts in Table 2.

[0150] According to a preferred embodiment, the measurement of the expression of the target genes is carried out at the level of the mRNA transcripts, and preferably at the level of the transcripts chosen from the transcripts (NCBI database) NM_023068.4, NM_001367089.1, NM 005101.4, NM_017912.4, NM 001165136.2, NM_017565.4, NM_001243746.2, NM_002424.3, NM_001304442.2, NM 001304441.2, NM_001039702.3, NM_018324.3, NM 004633.4, NM_001261419.2, NM_003256.4, NM_004171.4, NM_001195728.3, NM_001252652.2, NM_020415.4, NM_001385725.1, NM_001385726.1, NM_001385727.1, NM_001193374.2 and combinations thereof.

[0151] Any method known to those skilled in the art for measuring the level of gene expression, or a variation in gene expression, at the transcriptional level can be used within the framework of the method according to the invention.

[0152] Thus, the measurement can be carried out via a direct method allowing the presence of said transcript in the biological sample to be determined, or by indirect detection of the transcript after transformation of the latter into DNA.

[0153] The techniques commonly used to simultaneously measure the concentration of a large number of different types of messenger RNA are known to those skilled in the art and it is not necessary to give details thereof. Examples include DNA chips, CAGE, SAGE and, more recently, high-throughput RNA sequencing known as RNA-Seq.

[0154] According to the present description, gene expression at the transcriptional level can be measured by any known molecular detection method. Thus, the variation in gene expression can be measured by amplification, in particular via a Reverse Transcription-Polymerase Chain Reaction or RT-PCR, by sequencing (preferably by high-throughput sequencing) or by hybridization techniques (for example with hybridization microarrays or by techniques of the NanoString® nCounter® type). All these methods are also well known to those skilled in the art and it is not necessary to detail them here.

[0155] According to a particular embodiment, the determination of gene expression can be carried out in the following manner: (1) extraction of total RNA from a blood sample or PBMCs and carrying out a reverse transcription step in order to obtain the different complementary DNAs of the different messenger RNAs initially present in the sample or PBMCs (or cDNA),

[0156] (2) specific amplification of cDNAs. In this case, the specific reagent used includes at least one gene-specific amplification primer. This step can be carried out by a PCR-type amplification reaction or by any other suitable amplification technique,

[0157] (3) determination of gene expression by quantifying cDNAs.

[0158] According to a preferred embodiment, the measurement of gene expression is carried out by RT-PCR, preferably quantitative or semi-quantitative RT-PCR, or by nested PCR, for example using FilmArray® technology (Poritz et al. 2011) or Fluidigm's Biomark™ platform. According to this embodiment, expression is measured at the level of the mRNA transcripts of the target genes.

[0159] The person skilled in the art is in fact able to determine the sequences of the primers or pairs of primers necessary for the amplification of the transcripts of the target genes, and possibly of the additional target genes defined later in the description, to determine their respective expression levels. Indeed, numerous tools are available, for example Geneious or Primer 3, said sequences can then be adjusted if necessary by the person skilled in the art.

[0160] Measuring the expression level allows to determine the quantity of transcripts in the biological sample or also to give a derived value.

[0161] According to a particular embodiment, the level of expression of the target genes of the signature is a value derived or normalized from the quantity of transcripts, in particular mRNA, of said target genes.

[0162] According to a particular embodiment, the gene expression is normalized relative to the expression of one or more housekeeping genes (or reference genes) according to methods known to those skilled in the art. Thus, expression is normalized using one or more of the following housekeeping genes: DECRI (chromosomal location: chr8, 90001352-90053633), HPRT1 (chromosomal location: chrX, 134452842- 134520513) and PPIB (chromosomal location: chrl5:64155812-64163205), RPLP0 (chromosomal location: chrl2, 120196699-120201111), PPIA (chromosomal location: chr7, 44795960- 44803117), GLYR1 (chromosomal location: chrl6, 4803203-4847288), RANBP3 (chromosomal location: chrl7, 4803203-4847288), and RANBP4 (chromosomal location: chrl5, 4803203-4847288). chromosomal location: chrl9, 5916139-5978140), B2M (chromosomal location: chrl5, 44711492-44718145), IBP (chromosomal location: chr6, 170554369-170572859), GAPDH (chromosomal location: chrl2, 6534517-6538371) and ACTB (chromosomal location: chrl4, 5527148-5530601).The chromosomal locations are given according to GRCh38 / hg38. Preferably, the expression is normalized using one or more housekeeping genes selected from: DECRI, HPRT1, PPIB, GAPDH, ACTB and combinations thereof, more preferably, selected from DECRI, HPRT1, PPIB and combinations thereof.

[0163] In such a case, the reference level used is also standardized beforehand, in the same way. The standardization, whether for the reference level or for the transcript level of the biological sample to be tested, is carried out before the comparison, in particular before calculating a ratio between the transcript level of the said sample to be tested and the reference level. When a threshold value different from a reference level is used to issue a conclusion, this standardization may be taken into account when choosing the threshold value.

[0164] In the case where the level of gene transcript(s) is normalized with respect to the level of transcripts of one or more housekeeping genes, of course, this implies that the present method includes the determination of the level of transcripts of the housekeeping gene(s) used for normalization.

[0165] Generally speaking, according to the method of the present invention, and whatever its embodiments, the level of expression of a target gene (preferably the normalized expression) in the biological sample of the subject is compared to a predetermined expression value of this same gene (preferably the normalized expression) in a reference biological sample. This comparison makes it possible to obtain the variation in the expression of said target gene measured according to the present method.

[0166] For a given target gene, the reference expression value corresponds to a level of expression of transcripts of said gene obtained from a reference biological sample from a subject having an infection of a determined nature. The reference biological sample is of the same nature as the biological sample to be tested or at least of a compatible nature to constitute a reference for determining the level of expression of the target genes. Advantageously, and in particular for the embodiments below, the reference value for a given gene corresponds to the average of the level of mRNA transcripts of said gene obtained from reference biological samples from a population of subjects presenting an infection.

[0167] For the purposes of this description, the expression "reference value" or "predetermined reference value" is synonymous with the expressions "control value" or "threshold value", and serves as a point of comparison to determine whether the level of expression of a target gene is decreased or increased.

[0168] According to a particular embodiment, the reference value of the target genes corresponds to the level of expression of the mRNA transcripts of said genes obtained from a reference biological sample from a subject having a bacterial infection.

[0169] According to a particular embodiment, the reference value of the target genes corresponds to the level of expression of the mRNA transcripts of said genes obtained from a reference biological sample from a subject having a viral infection.

[0170] The comparison may be carried out by any method known to the person skilled in the art and may, for example, involve the calculation of a ratio or a difference. Advantageously, in the context of the present method, the comparison(s) and the issuing of a conclusion as to the nature of the infection in the subject from whom the biological sample originates is carried out by an automated technique, carried out by a computer or computer-assisted.

[0171] Thus, the viral or bacterial nature of the subject's infection is determined when comparisons of the expression levels of the target genes with their respective reference values ​​make it possible to identify a statistically significant difference, in other words, a variation in said expression level. Consequently, we will speak of overexpression when a significantly increased expression is highlighted, and conversely of underexpression, when a significantly decreased expression is highlighted. The person skilled in the art is able to determine the statistical test to be used to determine this reference value with which the expression level of the target genes must be compared. The exemplary embodiments present one of the possible methods.

[0172] According to a first embodiment of the invention, the reference expression value of each target gene is determined from a reference biological sample from a pool of biological samples from subjects suffering from a bacterial infection. Preferably, in the method according to the invention, the reference expression value of the target genes corresponds to the respective expression of said target genes in a reference biological sample obtained from a subject having a bacterial infection. Thus, it may be concluded that there is a viral infection when the comparison of the level of expression of the target genes at the level of the mRNA transcripts with respect to the respective reference values ​​highlights at least one variation in expression chosen from:

[0173] - overexpression of SIGLEC1,

[0174] - overexpression of ISG15,

[0175] - overexpression of HERC6,

[0176] - overexpression of RSAD2,

[0177] - overexpression of IFI27,

[0178] - overexpression of OAS1,

[0179] - overexpression of IFIT1, and

[0180] - an overexpression of IFI44L, and at least one other expression variation chosen from:

[0181] - underexpression of SLC1A2,

[0182] - an underexpression of IL1R2,

[0183] - underexpression of FAM20A,

[0184] - a sub-expression of OLAH,

[0185] - an underexpression of RETN, and

[0186] - an underexpression of MMP8.

[0187] According to a second embodiment of the invention, the reference value of each target gene is determined from a reference biological sample from a pool of biological samples from subjects suffering from a viral infection. Thus, it can be concluded that there is an infection of a bacterial nature when the results of the comparison of the expression of the target genes highlight at least two variations chosen from the following variations:

[0188] - an underexpression of SIGLEC1,

[0189] - an underexpression of ISG15, - an underexpression of HERC6,

[0190] - an underexpression of RSAD2,

[0191] - a sub-expression of IFI27,

[0192] - an underexpression of OAS1,

[0193] - an underexpression of IFIT1, and

[0194] - a sub-expression of IFI44L, and at least one other expression variation chosen from:

[0195] - overexpression of SLC1A2,

[0196] - overexpression of IL1R2,

[0197] - overexpression of FAM20A,

[0198] - an overexpression of OLAH,

[0199] - overexpression of RETN, and

[0200] - overexpression of MMP8.

[0201] The person skilled in the art is able to opt for one or other of the variants depending on the reference biological samples available. The reference biological sample is advantageously a pool of biological samples from subjects having a bacterial infection or a pool of biological samples from subjects having a viral infection.

[0202] For all the particular embodiments below, the conclusion as to the nature of the infection is made by taking into account the overexpression / underexpression of the different target genes highlighted from the biological sample of the subject, and as defined previously in one or other of the two variant embodiments.

[0203] According to a particular embodiment, step (a) comprises or consists of measuring the expression of at least one viral target gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0204] According to another particular embodiment, step (a) comprises or consists of measuring the expression of a single viral target gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably, of two or three bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0205] According to another particular embodiment, step (a) comprises or consists of measuring the expression of two viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLCl A2, and preferably, of two or three bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0206] According to another particular embodiment, step (a) comprises or consists of measuring the expression of three viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0207] According to another particular embodiment, step (a) comprises or consists of measuring the expression of four viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0208] According to another particular embodiment, step (a) comprises or consists of measuring the expression of five viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0209] According to another particular embodiment, step (a) comprises or consists of measuring the expression of six viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0210] According to another particular embodiment, step (a) comprises or consists of measuring the expression of seven viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0211] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the eight viral target genes SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and of two, three, four, five or six bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0212] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene SIGLEC1 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

[0213] According to a preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of the viral target gene SIGLEC1 and at least three selected bacterial target genes SLC1A2, IL1R2, OLAH, FAM20A and RETN.

[0214] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene ISG15 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A. According to another particular embodiment, the measuring step comprises or consists of measuring the expression of the viral gene HERC6 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

[0215] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFIT1 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0216] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI44L and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0217] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene RSAD2 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0218] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene OAS1 and one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0219] According to a preferred embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI27 and one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably from IL1R2, OLAH, FAM20 and RETN.

[0220] According to another preferred embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, and optionally of at least one other viral gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L, and of two bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH, FAM20A, IL1R2 and MMP8.

[0221] According to another preferred embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, the bacterial target gene OLAH and at least one other bacterial target gene selected from SLC1A2, IL1R2, FAM20A, RETN and MMP8.

[0222] According to another particular embodiment, step (a) comprises or consists of measuring the expression of a combination of two target genes chosen from the combinations in table 6, and preferably those which have a performance in terms of area under the ROC curve of the model of at least 0.86, and very particularly, of at least 0.88.

[0223] According to a preferred variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of a viral target gene and a bacterial target gene, said combination being chosen from the following combinations: SIGLEC1 IL1R2, IFI44L OLAH and IFI27 1L1R2.

[0224] According to another embodiment, step (a) comprises or consists of measuring the expression of a combination of two target genes chosen from the following combinations: SIGLEC1 IL1R2; SIGLEC1 FAM20A; HERC6 IL1R2; SIGLEC1 OLAH; HERC6 OLAH; ISG15 IL1R2; SIGLEC1 RETN; HERC6 FAM20A; SLC1A2 OLAH; HERC6 RETN; SIGLEC1_SLC1A2; ISG15 OLAH; SIGLEC1 MMP8; HERC6 MMP8; IL1R2 OLAH; IL1R2 FAM20A; SIGLEC1_HERC6; HERC6 SLC1A2; SIGLEC1 ISG15; FAM20A OLAH; ISG15 FAM20A; SLC1A2 IL1R2; ISG15 RETN; ISG15 MMP8 and ISG15 SLC1A2, and preferably selected from the following gene combinations: SIGLEC1 IL1R2; SIGLEC1_FAM2OA; HERC6 IL1R2; SIGLEC1 OLAH and HERC6 OLAH.

[0225] According to another particular embodiment, step (a) comprises or consists of the measurement of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, of the bacterial target gene OLAH, and of at least one other bacterial target gene chosen from FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from FAM20A, IL1R2 and MMP8.

[0226] According to another particular embodiment, step (a) step (a) comprises or consists of the measurement of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, of the bacterial target gene FAM20A, and of at least one other bacterial target gene chosen from OLAH, IL1R2, MMP8, RETN and SLC1A2, preferably from OLAH, IL1R2 and MMP8.

[0227] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and ISG15, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0228] According to a particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and HERC6, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0229] According to a particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0230] According to a preferred embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0231] According to a variant of this preferred embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and IFI27, and of two to four bacterial target genes chosen from OLAH, FAM20A, IL1R2 and MMP8.

[0232] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0233] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably, chosen from OLAH and FAM20A. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0234] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and HERC6, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0235] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0236] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably, chosen from OLAH and FAM20A.

[0237] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0238] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0239] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0240] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0241] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH and FAM20A.

[0242] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0243] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0244] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0245] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0246] According to a particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0247] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0248] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0249] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0250] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0251] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes OAS1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0252] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes OAS1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0253] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI44L and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0254] According to another particular embodiment, the measuring step comprises or consists of the measurement of at least one viral target gene chosen from SIGLEC1, ISG15 and HERC6, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. Preferably, according to this embodiment, the measuring step comprises or consists of the measurement of at least one viral target gene chosen from SIGLEC1, ISG15 and HERC6, and of at least one target gene chosen from IL1R2, OLAH, and FAM20A.

[0255] According to another particular embodiment, the measuring step comprises or consists of the measurement of at least one viral target gene selected from RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and at least one bacterial target gene selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. Preferably, according to this embodiment, the measuring step comprises or consists of the measurement of at least one viral target gene selected from RSAD2, IFI27, OAS1, IFIT1 and IFI44L, and at least one bacterial target gene selected from IL1R2, OLAH, and FAM20A.

[0256] According to another preferred embodiment, the measuring step comprises or consists of the measurement of at least one viral target gene chosen from SIGLEC1, ISG15 and HERC6, and at least two bacterial target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN and MMP8, and preferably IL1R2, OLAH and FAM20A.

[0257] According to a variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene SIGLEC1 and at least two bacterial target genes chosen from the group consisting of OLAH, SLC1A2, IL1R2, FAM20A, RETN and MMP8.

[0258] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene HERC6 and at least two bacterial target genes chosen from the group consisting of OLAH, SLC1A2, IL1R2, FAM20A, RETN and MMP8.

[0259] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene ISG15 and at least two bacterial target genes chosen from the group consisting of OLAH, SLC1A2, IL1R2, FAM20A, RETN and MMP8.

[0260] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene SIGLEC1 and the bacterial target gene OLAH, and of at least one other target gene chosen from the group consisting of ISG15, HERC6, SLC1A2, IL1R2, FAM20A, RETN and MMP8.

[0261] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target gene SIGLEC1 and the bacterial target gene IL1R2, and of at least one other target gene chosen from ISG15, HERC6, SLC1A2, OLAH, FAM20A, RETN and MMP8, and preferably chosen from SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0262] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and HERC6, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0263] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0264] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0265] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0266] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, ISG15 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0267] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, HERC6 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0268] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, HERC6 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0269] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, HERC6 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0270] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, HERC6 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0271] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC 1, HERC6 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0272] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC 1, RSAD2 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0273] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, RSAD2 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0274] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, RSAD2 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, RSAD2 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0275] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC 1, IFI27 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0276] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, IFI27 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0277] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0278] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, IFIT1 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0279] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC 1, OAS1 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0280] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes SIGLEC1, IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0281] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, HERC6 and RSAD2, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0282] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, HERC6 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0283] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, HERC6 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0284] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, HERC6 and IFIT1, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, HERC6 and IFI44L, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0285] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, RSAD2 and IFI27, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0286] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, RSAD2 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0287] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, RSAD2 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0288] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, RSAD2 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0289] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, IFI27 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0290] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, IFI27 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0291] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0292] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, OAS1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0293] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, OAS1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0294] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes ISG15, IFIT1 and IFI44L, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, RSAD2 and IFI27, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0295] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, RSAD2 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0296] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, RSAD2 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0297] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, RSAD2 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0298] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, IFI27 and OAS1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0299] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, IFI27 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0300] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0301] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, OAS1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0302] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, OAS 1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0303] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes HERC6, IFI44L and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0304] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, OAS1 and IFI27, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, IFI27 and IFIT1, and of one or more bacterial target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0305] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, IFI27 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0306] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, OAS1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0307] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, OAS1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0308] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes RSAD2, IFIT1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0309] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27, OAS1 and IFIT1, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0310] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27, OAS1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0311] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27, IFIT1 and IFI44L and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0312] According to another particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes OAS1, IFIT1 and IFI44L, and of one or more bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0313] According to another particular embodiment, step (a) comprises or consists of measuring the expression of a combination of three target genes chosen from those listed in Table 7, and preferably those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.86, at least 0.88, and most particularly, at least 0.90.

[0314] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations: SIGLEC1JL1R2 FAM20A, HERC6 IL 1R2 FAM20 A, SIGLEC1_SLC1A2_OLAH,

[0315] SIGLEC1 HERC6 IL1R2, SIGLEC1 FAM20A OLAH, SIGLEC1 JL1R2 MMP8, SIGLEC1 ISG15 IL1R2, SIGLEC1 SLC1A2 IL1R2, SIGLEC1_IL1R2_OLAH, SIGLEC1_SLC1A2_FAM2OA,

[0316] SLC1A2 FAM20A MMP8, SLC1A2 RETN MMP8, and FAM20A_RETN_MMP8. Preferably, according to this variant, the measuring step comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations: SIGLEC 1 IL1R2 FAM20 A, HERC6_IL1R2_FAM2OA, SIGLEC1 SLC1A2 OLAH, SIGLEC 1 HERC6 IL1R2, SIGLEC 1 FAM20A OL AH,

[0317] SIGLEC 1 IL1R2 MMP8, SIGLEC1_ISG15_IL1R2, SIGLEC 1 SLC1A2 IL1R2, SIGLEC 1 IL1R2 OLAH, SIGLEC1 SLC1A2 FAM20A and HERC6 FAM20A OLAH, and more preferably among SIGLEC 1 IL1R2 FAM20 A, HERC6 IL1R2 FAM20A and SIGLEC 1 SLC1A2 OL AH.

[0318] According to another variant of a particular embodiment, step (a) comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations: IFI27 OLAH FAM20A, IFI27 IL1R2 FAM20A, IFI27 OLAH MMP8, IFI27 HERC6 OLAH,

[0319] IFI27 IL1R2 OLAH, IFI27 ISG15 OLAH, IFI27 OLAH RETN, IFI27 SLC1A2 OLAH,

[0320] IFI27 SIGLEC 1 OLAH, IFI27 SIGLEC 1JL1R2, IFI27 IFI44L OLAH, IFI27 IFIT1 OLAH,

[0321] IFI27 OAS1 OLAH, IFI27 HERC6 IL1R2, RSAD2 IFI27 OLAH, IFI27 IL1R2 RETN,

[0322] IFI27 IFI44L IL1R2, IFI27 IFIT1 IL1R2, IFI27 ISG15 IL1R2 and RSAD2 IFI27 IL1R2.

[0323] According to another particular embodiment, step (a) comprises or consists of measuring the expression of at least four target genes.

[0324] According to a variant of this embodiment, the measuring step comprises or consists of the measurement of at least two target genes selected from SIGLEC1, ISG15 and HERC6, and of at least two target genes selected from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably IL1R2, OLAH and FAM20A. According to another variant of this embodiment, the measuring step comprises or consists of the measurement of SIGLEC1 and of at least three target genes selected from SLC1A2, IL1R2, OLAH, FAM20A and RETN.

[0325] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and IL1R2, and of at least two other target genes chosen from ISG15, HERC6, SLC1 A2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, OLAH and FAM20A.

[0326] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and HERC6, and of at least two other target genes chosen from ISG15, IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8. According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, IL1R2 and FAM20A, and of at least one other target gene chosen from ISG15, HERC6, SLC1A2, OLAH, RETN and MMP8.

[0327] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and SLC1A2, and of at least two other target genes chosen from ISG15, IL1R2, HERC6, OLAH, FAM20A, RETN and MMP8, and preferably IL1R2, OLAH, FAM20A and MMP8.

[0328] According to another preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, of another viral target gene chosen from HERC6, SIGLEC1, IFI44L and ISG15, of the bacterial target gene FAM20A and of another bacterial target gene chosen from OLAH and IL1R2.

[0329] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of four target genes chosen from those listed in Table 8, and preferably those in this table which have a performance in terms of area under the ROC curve of the model of at least 0.86, at least 0.88, and most particularly, at least 0.90.

[0330] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of a combination of four target genes chosen from the combinations presented in Table 3 below:

[0331] [Table 3]

[0332]

[0333] Preferably, according to this variant, the measuring step comprises or consists of measuring the expression of a combination of four target genes chosen from the following combinations: SIGLEC 1_IL 1R2 FAM20 A MMP8, SIGLEC 1 HERC6 IL 1R2 F AM20 A,

[0334] SIGLEC 1 ISG15_IL 1R2 FAM20A, SIGLEC 1_IL 1R2 FAM20 A OL AH, SIGLEC 1_IL 1R2 FAM20 A RETN, SIGLEC 1 SLC 1 A2 IL 1R2 F AM20 A, SIGLEC 1 SLC 1 A2_F AM20 A_OL AH,

[0335] ISG15_HERC6_IL1R2_FAM2OA, SIGLEC 1_FAM20A_OLAH_MMP8, and HERC6_IL1R2_FAM20A_OLAH.

[0336] According to another particular embodiment, step (a) comprises or consists of measuring the expression of at least five target genes.

[0337] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of at least two target genes chosen from SIGLEC1, ISG15 and HERC6 and at least three other target genes chosen from IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0338] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, ISG15 and HERC6 and of at least two other target genes chosen from IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8, preferably from IL1R2, OLAH and FAM20A.

[0339] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and ISG15 and at least three other target genes chosen from HERC6, IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8, preferably from IL1R2, OLAH, FAM20A and MMP8.

[0340] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and IL1R2 and at least three other target genes chosen from HERC6, ISG15, SLC1A2, OLAH, FAM20A, RETN and MMP8, preferably from OLAH, SLC1A2, FAM20A and MMP8.

[0341] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and MMP8 and at least three other target genes chosen from HERC6, ISG15, SLC1 A2, OLAH, FAM20A, RETN and IL1R2, preferably from OLAH, SLC1A2, FAM20A and IL1R2.

[0342] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and HERC6 and at least three other target genes chosen from ISG15, IL1R2, SLC1 A2, OLAH, FAM20A, RETN and MMP8, preferably from IL1R2, OLAH, FAM20A and MMP8.

[0343] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, FAM20A and MMP8, and of at least two other target genes chosen from IL1R2, ISG15, HERC6, SLC1A2, OLAH, and RETN, preferably from IL1R2, ISG15, SLC1A2 and OLAH.

[0344] According to a variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, IL1R2 and HERC6 and of at least two other target genes chosen from ISG15, SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0345] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, IL1R2 and ISG15 and of at least two other target genes chosen from HERC6, SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0346] According to another variant of this embodiment, the measuring step comprises or consists of measuring the expression of a combination of five target genes chosen from the combinations presented in Table 4 below:

[0347] [Table 4]

[0348]

[0349] Preferably, according to this variant, the measuring step comprises or consists of measuring the expression of a combination of five target genes chosen from the following combinations: SIGLEC1_HERC6_IL1R2_FAM2OA_MMP8, SIGLEC1 _IL1R2_FAM20A_OLAH_MMP8;

[0350] SIGLEC1_ISG15_IL1R2_FAM2OA_MMP8 ; SIGLEC1_IL1R2_FAM2OA_RETN_MMP8 ;

[0351] SIGLEC1_SLC1A2_IL1R2_FAM2OA_MMP8 ; SIGLEC1 JSG15_HERC6_IL1R2_FAM2OA ;

[0352] SIGLEC1_HERC6_IL1R2_FAM20A_OLAH ; SIGLEC1_SLC1A2_FAM20A_OLAH_MMP8 and SIGLEC1_ISG15_IL1R2_FAM20A_OLAH.

[0353] According to a preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of the viral target gene IFI27, of two other viral target genes chosen from SIGLEC1, HERC6, OAS1 and IFIT1, of the bacterial target gene FAM20A and of another bacterial target gene chosen from OLAH, IL1R2 and MMP8.

[0354] According to another preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of a combination of five target genes chosen from those listed in Table 9, and preferably those in this table which have a performance in terms of area under the ROC curve of the model of at least 0.86, at least 0.88, and most particularly, at least 0.90.

[0355] According to another preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, and the bacterial target genes FAM20A, IL1R2 and MMP8.

[0356] According to another particular embodiment, step (a) comprises or consists of measuring the expression of at least six target genes.

[0357] According to a variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, ISG15 and HERC6 and of at least three other target genes chosen from IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0358] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, FAM20A and MMP8 and at least three other target genes chosen from ISG15, HERC6, IL1R2, SLC1A2, OLAH, and RETN.

[0359] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, ISG15 and SLC1 A2, and of at least three other target genes chosen from HERC6, IL1R2, OLAH, FAM20A, MMP8 and RETN. According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and IL1R2, and of at least four other target genes chosen from HERC6, SLC1 A2, OLAH, FAM20A, RETN and MMP8.

[0360] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and HERC6, and of at least four other target genes chosen from ISG15, IL1R2, SLC1A2, OLAH, FAM20A, RETN and MMP8.

[0361] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and MMP8, and of at least four other target genes chosen from HERC6, ISG15, IL1R2, SLC1A2, OLAH, FAM20A, and RETN.

[0362] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and OLAH, and of at least four other target genes chosen from HERC6, ISG15, IL1R2, SLC1A2, MMP8, FAM20A, and RETN.

[0363] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of a combination of six target genes chosen from the following combinations:

[0364] SIGLEC 1 _IS G 15_IL 1R2 F AM20 A OL AH MMP8 ;

[0365] SIGLEC 1 HERC6 IL 1R2 FAM20 A OLAH MMP8;

[0366] SIGLEC 1 ISG 15 HERC6 IL 1R2 F AM20A MMP8 ;

[0367] SIGLEC 1 SLC 1 A2 IL 1R2 FAM20 A OL AH MMP8 ;

[0368] ABBREVIATION 1 HERC6 IL 1R2 FAM20 A RETN MMP8 ;

[0369] SIGLEC1_ISG15_IL1R2_FAM2OA_RETN_MMP8 ;

[0370] SIGLEC 1_IL1R2_FAM20A_OLAH_RETN_MMP8 ;

[0371] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 FAM20A MMP8 ;

[0372] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 F AM20 A MMP8 ;

[0373] SIGLEC 1 SLC 1 A2 IL 1R2 FAM20 A RETN MMP8 ;

[0374] SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH_MMP8 ;

[0375] SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_OLAH ;

[0376] SIGLEC 1 HERC6 SLC 1 A2_F AM20 A OL AH MMP8 ;

[0377] SIGLEC 1 ISG15_IL 1R2 FAM20 A OL AH RETN ;

[0378] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 FAM20A OL AH ;

[0379] SIGLEC 1 SLC 1 A2 IL 1R2 F AM20A OLAH RETN ;

[0380] SIGLEC 1 SLC 1 A2_F AM20 A OL AH RETN MMP8 ;

[0381] SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH ;

[0382] SIGLEC1_ISG15_HERC6_IL1R2_FAM2OA_RETN ;

[0383] SIGLEC 1 HERC6 IL 1R2 FAM20A OLAH RETN ;

[0384] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM2OA ;

[0385] SIGLEC1_ISG15_SLC1A2_IL1R2_FAM2OA_RETN ;

[0386] SIGLEC 1_HERC6_FAM20A_OLAH_RETN_MMP8 ;

[0387] SIGLEC 1 ISG 15 HERC6 FAM20 A OLAH MMP8; SIGLEC 1 ISG15 HERC6 SLC 1 A2 FAM20A OL AH ;

[0388] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 FAM20A RETN ;

[0389] SIGLEC1_ISG15_FAM20A_OLAH_RETN_MMP8 ;

[0390] SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH_RETN ;

[0391] ISG15 HERC6 IL 1R2 FAM20 A OLAH MMP8;

[0392] SIGLEC 1 ISG15_HERC6_FAM20A_RETN_MMP8 ;

[0393] ISG15_HERC6_IL1R2_FAM2OA_RETN_MMP8 ;

[0394] SIGLEC 1 HERC6 SLC 1 A2_F AM20 A_OL AH RETN ;

[0395] ISG15_HERC6_IL1R2_FAM20A_OLAH_RETN ;

[0396] SIGLEC1_ISG15_HERC6_FAM20A_OLAH_RETN ;

[0397] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 OLAH MMP8;

[0398] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 OLAH MMP8;

[0399] SIGLEC 1 ISG 15 HERC6 SLC 1 A2 OLAH MMP8;

[0400] HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;

[0401] SIGLEC 1 HERC6 SLC 1 A2_F AM20 A RETN MMP8 ;

[0402] ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH ;

[0403] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_OLAH ;

[0404] SIGLEC1_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;

[0405] SIGLEC 1 ISG15 SLC 1 A2 FAM20 A RETN MMP8 ;

[0406] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 OL AH RETN ;

[0407] HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;

[0408] SIGLEC 1 ISG15 HERC6 SLC 1A2 FAM20A RETN ;

[0409] ISG15_HERC6_SLC1A2_IL1R2_FAM2OA_RETN ;

[0410] SIGLEC 1 _IS G 15 HERC6 IL 1R2 RETN MMP8 ;

[0411] SIGLEC1_ISG15_SLC1A2_OLAH_RETN_MMP8 ;

[0412] SIGLEC 1_HERC6_IL1R2_OLAH_RETN_MMP8 ;

[0413] SIGLEC 1 _IS G 15 HERC6 IL 1R2 OL AH MMP8;

[0414] SIGLEC 1 HERC6 SLC 1 A2 OL AH RETN MMP8 ;

[0415] HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;

[0416] ISG15 HERC6 SLC 1 A2 IL 1R2 F AM20A MMP8 ;

[0417] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_MMP8 ;

[0418] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 OL AH RETN ;

[0419] ISG15_HERC6_FAM20A_OLAH_RETN_MMP8 ;

[0420] SIGLEC1_ISG15_HERC6_SLC1A2_OLAH_RETN ;

[0421] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 RETN MMP8 ;

[0422] ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN ;

[0423] HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;

[0424] SIGLEC1_ISG15_HERC6_SLC1A2_FAM2OA_MMP8 ;

[0425] ISG15_HERC6_SLC1A2_FAM20A_OLAH_MMP8 ; SIGLEC1_ISG15_SLC1A2_IL1R2_RETN_MMP8 ;

[0426] HERC6_SLC1A2_IL1R2_FAM2OA_RETN_MMP8 ;

[0427] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_RETN ;

[0428] SIGLEC1_ISG15_IL1R2_OLAH_RETN_MMP8 ;

[0429] ISG15 SLC 1 A2 IL 1R2 FAM20 A OLAH MMP8;

[0430] SIGLEC 1 ISG15 HERC6 IL 1R2 OL AH RETN ;

[0431] ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;

[0432] SIGLEC1_ISG15_HERC6_OLAH_RETN_MMP8 ;

[0433] ISG15_HERC6_IL1R2_OLAH_RETN_MMP8 ;

[0434] ISG15 HERC6 SLC 1 A2 IL 1R2 OLAH RETN ;

[0435] ISG15_HERC6_SLC1A2_OLAH_RETN_MMP8 ;

[0436] ISG15_HERC6_SLC1A2_IL1R2_OLAH_MMP8 ;

[0437] HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;

[0438] ISG15_SLC1A2_IL1R2_FAM2OA_RETN_MMP8 ;

[0439] ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;

[0440] ISG15_HERC6_SLC1A2_FAM2OA_RETN_MMP8 ;

[0441] ISG15 HERC6 SLC 1 A2 IL 1R2 RETN MMP8 ;

[0442] ISG15_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;

[0443] SIGLEC 1 ISG 15 HERC6 SLC 1 A2 RETN MMP8;

[0444] ISG15_SLC1A2_IL1R2_OLAH_RETN_MMP8 ; and SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8.

[0445] Preferably, according to this variant, the measuring step comprises or consists of measuring the expression of a combination of six target genes chosen from the following combinations:

[0446] SIGLEC 1 _IS G 15_IL 1R2 F AM20 A OL AH MMP8 ;

[0447] SIGLEC 1 HERC6 IL 1R2 FAM20 A OLAH MMP8;

[0448] SIGLEC 1 ISG 15 HERC6 IL 1R2 F AM20A MMP8;

[0449] SIGLEC 1 SLC 1 A2 IL 1R2 F AM20 A OL AH MMP8 ;

[0450] SIGLEC 1 HERC6 IL 1R2 FAM20 A RETN MMP8;

[0451] SIGLEC1 JSG15_IL1R2_FAM2OA_RETN_MMP8 ; And

[0452] SIGLEC 1 IL 1R2 FAM20 A OLAH RETN MMP8

[0453] According to a preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, of another viral target gene chosen from IFIT1, HERC6, ISG15 and ISG15, of the bacterial target genes FAM20A and MMP8, and of another bacterial target gene chosen from OLAH and ILlR2.

[0454] According to another preferred variant of this embodiment, step (a) comprises or consists of measuring the expression of a combination of six target genes chosen from those listed in Table 10, and preferably those in this table which have a performance in terms of area under the ROC curve of the model of at least 0.86, at least 0.88, and most particularly, at least 0.90. According to another particular embodiment, step (a) comprises or consists of measuring the expression of at least seven target genes.

[0455] According to a variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the target gene SIGLEC1 and six other target genes chosen from ISG15, HERC6, OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

[0456] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the target gene MMP8 and six other target genes chosen from ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and SIGLEC 1.

[0457] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and MMP8, and of at least four other target genes chosen from ISG15, HERC6, IL1R2, SLC1A2, OLAH, FAM20A, and RETN, preferably from ISG15, HERC6, IL1R2, OLAH, FAM20A, and RETN.

[0458] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1 and ISG15, and of five other target genes chosen from HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

[0459] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, ISG15 and HERC6, and of four other target genes chosen from SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

[0460] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, FAM20A and MMP8, and of at least three other target genes chosen from ISG15, HERC6, IL1R2, SLC1A2, OLAH and RETN, and preferably from ISG15, HERC6, IL1R2, OLAH and RETN.

[0461] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of the target genes SIGLEC1, FAM20A, IL1R2 and MMP8, and of at least two other target genes chosen from ISG15, HERC6, SLC1A2, OLAH and RETN, and preferably from ISG15, HERC6, OLAH and RETN.

[0462] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of seven target genes chosen from the following combinations:

[0463] SIGLEC 1 ISG15 HERC6 IL 1R2 FAM20 A OLAH MMP8;

[0464] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 FAM20 A OLAH MMP8;

[0465] IGLEC 1 HERC6 SLC 1 A2 IL 1R2 F AM20 A OL AH MMP8 ;

[0466] SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;

[0467] SIGLEC 1 ISG15 HERC6 IL 1R2 FAM20 A RETN MMP8;

[0468] SIGLEC 1 HERC6 IL 1R2 F AM20A OL AH RETN MMP8 ;

[0469] SIGLEC 1 ISG15 HERC6 SLC 1 A2 IL 1R2 FAM20 A MMP8;

[0470] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 FAM20 A RETN MMP8 ;

[0471] SIGLEC 1 SLC 1 A2 IL 1R2 FAM20A OL AH RETN MMP8 ; SIGLEC1_HERC6_SLC1A2_IL1R2_FAM2OA_RETN_MMP8 ;

[0472] SIGLEC 1 ISG15 HERC6 SLC 1 A2 FAM20A OLAH MMP8;

[0473] SIGLEC 1 ISG15 SLC 1 A2 FAM20A OL AH RETN MMP8 ;

[0474] SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;

[0475] SIGLEC1_HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8;

[0476] SIGLEC 1 ISG 15 HERC6 IL 1R2 F AM20A OLAH RETN ;

[0477] SIGLEC 1 ISG 15 HERC6 SLC 1 A2 IL 1R2 FAM20A OL AH;

[0478] SIGLEC 1 ISG15 HERC6 FAM20 A OLAH RETN MMP8 ;

[0479] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 FAM20 A OLAH RETN;

[0480] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM2OA_RETN ;

[0481] SIGLEC 1 ISG15 HERC6 SLC 1 A2 FAM20 A OLAH RETN ;

[0482] ISG15 HERC6 IL 1R2 FAM20 A OL AH RETN MMP8;

[0483] SIGLEC 1 ISG15 HERC6 SLC 1 A2 FAM20 A RETN MMP8;

[0484] SIGLEC 1 ISG15 HERC6 SLC 1A2 IL 1R2 OLAH MMP8 ;

[0485] SIGLEC1_ISG15_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;

[0486] ISG15_HERC6_SLC1A2_IL1R2_FAM2OA_RETN_MMP8 ;

[0487] ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;

[0488] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 OL AH RETN MMP8 ;

[0489] ISG15 HERC6 SLC 1 A2 IL 1R2 FAM20 A OLAH RETN ;

[0490] HERC6 SLC 1 A2 IL 1R2 F AM20 A OL AH RETN MMP8 ;

[0491] SIGLEC1_ISG15_HERC6_IL1R2_OLAH_RETN_MMP8 ;

[0492] SIGLEC1_ISG15_HERC6_SLC1A2_OLAH_RETN_MMP8 ;

[0493] ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;

[0494] SIGLEC 1 ISG15 HERC6 SLC 1A2 IL 1R2 OL AH RETN ;

[0495] SIGLEC 1 ISG15 HERC6 SLC 1A2 IL 1R2 RETN MMP8 ;

[0496] ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ; and ISG15_HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8.

[0497] Preferably, according to this variant, the measuring step comprises or consists of measuring the expression of seven target genes chosen from the following combinations:

[0498] SIGLEC 1 ISG15 SLC 1A2 IL 1R2 FAM20 A OLAH MMP8;

[0499] IGLEC 1 HERC6 SLC 1 A2 IL 1R2 F AM20 A OL AH MMP8 ;

[0500] SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;

[0501] SIGLEC 1 ISG15 HERC6 IL 1R2 FAM20 A RETN MMP8;

[0502] SIGLEC 1 HERC6 IL 1R2 F AM20A OL AH RETN MMP8 ;

[0503] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM2OA_MMP8 ; And

[0504] SIGLEC1_ISG15_SLC1A2_IL1R2_FAM2OA_RETN_MMP8.

[0505] According to a preferred variant of this particular embodiment, step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, and of two other viral target genes chosen from IFIT1, OAS1, HERC6 and ISG15, of the bacterial target genes FAM20A and MMP8, and of another bacterial target gene chosen from OLAH and IL1R2

[0506] According to another preferred variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of seven target genes chosen from those listed in Table 11, and preferably those in this table which have a performance in terms of area under the ROC curve of the model of at least 0.86, at least 0.88, and most particularly, at least 0.90.

[0507] According to another particular embodiment, step (a) comprises or consists of measuring the expression of at least eight target genes.

[0508] According to a variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of SIGLEC1 and ISG15, and at least six other target genes chosen from HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

[0509] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of SIGLEC1, MMP8 and at least six other target genes chosen from HERC6, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, and RETN.

[0510] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of SIGLEC1, MMP8 and ISG15, and at least five other target genes chosen from HERC6, SLC1A2, IL1R2, FAM20A, OLAH, and RETN.

[0511] According to another variant of this particular embodiment, the measuring step comprises or consists of measuring the expression of a combination of eight target genes chosen from the following combinations:

[0512] SIGLEC 1 ISG15 HERC6 IL 1R2 FAM20 A OL AH RETN MMP8 ;

[0513] SIGLEC 1 ISG15 HERC6 SLC 1A2 IL 1R2 FAM20A OLAH MMP8;

[0514] SIGLEC 1 ISG15 SLC 1 A2 IL 1R2 FAM20 A OL AH RETN MMP8 ;

[0515] SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM2OA_RETN_MMP8 ;

[0516] SIGLEC 1 HERC6 SLC 1 A2 IL 1R2 F AM20A OL AH RETN MMP8 ;

[0517] SIGLEC 1 ISG15 HERC6 SLC 1 A2_F AM20A OL AH RETN MMP8 ;

[0518] SIGLEC 1 ISG15 HERC6 SLC 1A2 IL 1R2 FAM20A OLAH RETN ;

[0519] ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8, and

[0520] SIGLEC 1 ISG 15 HERC6 SLC 1 A2 IL 1R2 OL AH RETN MMP8.

[0521] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of eight target genes chosen from those listed in Table 12, and preferably, those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.87, at least 0.88, and most particularly, at least 0.89.

[0522] According to another particular embodiment, the method comprises a step of measuring the variation in the expression of at least nine target genes.

[0523] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of nine target genes chosen from those listed in Table 13, and preferably those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.87, at least 0.88, and most particularly, at least 0.89.

[0524] According to another particular embodiment, the method comprises a step of measuring the variation in the expression of the ten target genes.

[0525] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of ten target genes chosen from those listed in Table 14, and preferably those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.87, at least 0.88, and most particularly, at least 0.89.

[0526] According to another particular embodiment, the method comprises a step of measuring the variation in the expression of at least eleven target genes.

[0527] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of eleven target genes chosen from those listed in table 15, and preferably those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.86, and very particularly, of at least 0.87.

[0528] According to another particular embodiment, the method comprises a step of measuring the variation in the expression of at least twelve target genes.

[0529] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of twelve target genes chosen from those listed in table 16, and preferably those which exhibit a performance in terms of area under the ROC curve of the model of at least 0.86, and very particularly, of at least 0.87.

[0530] According to another particular embodiment, the method comprises a step of measuring the variation in the expression of at least thirteen target genes.

[0531] According to another variant of this particular embodiment, step (a) comprises or consists of measuring the expression of a combination of thirteen target genes chosen from those listed in table 17.

[0532] By "biological sample" is meant in this description any sample originating from a subject and which may be of different natures, such as blood or its derivatives, sputum, urine, stool, skin, cerebrospinal fluid, bronchoalveolar lavage fluid, abdominal cavity puncture fluid, saliva, gastric secretions, semen, seminal fluid, tears, spinal cord, trigeminal nerve ganglion, adipose tissue, lymphoid tissue, placental tissue, gastrointestinal tract tissue, genital tract tissue, or central nervous system tissue.

[0533] The expression "reference biological sample" or "control sample" refers to the biological sample from which the expression levels of the target genes, and possibly those of the additional genes, in the biological sample to be tested are compared. The reference biological sample is of the same nature as the biological sample to be tested or at least of a compatible nature to constitute a reference for determining the level of expression of the target genes. This sample comes from a subject with a bacterial or viral infection, or from a pool of biological samples all from patients with an infection of the same nature, namely viral or bacterial.

[0534] According to a particular embodiment, the reference biological sample is calibrated to contain the quantity of transcripts of at least two target genes, and optionally one or more additional genes, corresponding to the quantity or concentration representative of the level of expression measured in a pool of samples from subjects having a bacterial infection or a viral infection. In other words, the reference biological sample is calibrated to contain the average quantity of transcripts of said target genes obtained from a pool of samples from subjects having a bacterial infection or from subjects having a viral infection.

[0535] In particular, the biological sample may be a biological fluid, such as a blood sample or a blood-derived sample, which may in particular be chosen from whole blood (as collected venously, i.e. containing white and red cells, platelets and plasm(a), plasma, serum, as well as all types of cells extracted from blood, such as for example peripheral blood mononuclear cells (or PBMC, containing B lymphocytes, T lymphocytes, NK cells, dendritic cells and monocytes), subpopulations of B and T lymphocytes, purified monocytes, or neutrophils.

[0536] According to a preferred embodiment, the biological sample used in the method according to the invention is a blood sample, preferably a whole blood sample.

[0537] According to another particular embodiment, the subject is a patient within a hospital, preferably within the emergency department, the intensive care unit, in an intensive care unit (ICU) or in a continuing care unit, and in particular, a patient within the emergency department.

[0538] According to a preferred embodiment, the subject is a patient aged less than 6 years, preferably less than 4 years, and more preferably less than 2 years. According to this embodiment, the patient may be in the emergency department, and in particular in a pediatric emergency.

[0539] According to a particular embodiment, the method makes it possible to identify the nature of the infection with a sensitivity of at least 80%, 85%, 90% or at least 95%. The sensitivity corresponds to the probability of correctly identifying the viral or bacterial nature of the infection when the subject is infected and can be defined by the following formula: number of true positives

[0540] Sensitivity = - - - - - - - - - - - — - - - - — number of true positives + number of false negatives

[0541] According to a particular embodiment, the method makes it possible to identify the nature of the infection with a specificity of at least 80%, 85%, 90% or even at least 95%.

[0542] Specificity is the probability of misidentifying the viral or bacterial nature of the infection. In other words, of identifying the presence of a viral infection when it is actually a bacterial infection, or vice versa. Specificity can be defined by the following formula: number of true negatives

[0543] Specificity = - number of true negatives + number of false positives The sensitivity and specificity of a diagnostic test, such as the method according to the present invention, can also be summarized by means of a ROC curve (from the English “Receiver Operating Characteristics”), in particular the area under the ROC curve, which is well known to those skilled in the art.

[0544] Thus, the method according to the present description makes it possible to identify the viral or bacterial nature of an infection with a performance reflected by an area under the ROC curve of at least 0.85, at least 0.86, at least 0.87, at least 0.88, at least 0.89, and in particular at least 0.90 for the most efficient transcriptomic signatures.

[0545] Although the performance of the method according to the invention is entirely satisfactory, in certain situations, the measurement of the variation in expression of the target genes can be supplemented by the measurement of the variation in expression of additional genes.

[0546] Thus, the method according to the invention, in all its embodiments, can further comprise the measurement of the variation of at least one additional gene chosen from the following genes: PI3, EBI3, ADGRE1 and S100P.

[0547] These additional genes are also known to those skilled in the art and the chromosomal positions are given in Table 5 below:

[0548] [Table 5]:

[0549] In the same way as previously, for a given additional gene, the reference value corresponds to a level of expression of transcripts of said gene obtained from a reference biological sample from a subject presenting an infection. Advantageously, and in particular for the variants defined below, the reference value for a given additional gene corresponds to the average of the level of mRNA transcripts of said gene obtained from reference biological samples from a population of subjects presenting an infection.

[0550] According to a first variant, the reference value of each additional gene is determined from a reference biological sample from a subject suffering from a bacterial infection. Thus, it may be concluded that there is a viral infection when the comparison of the level of expression of the additional genes at the level of the mRNA transcripts with respect to the respective reference values ​​highlights at least one variation in expression chosen from:

[0551] - an underexpression of PI3,

[0552] - an underexpression of EBI3,

[0553] - an underexpression of ADGRE1, and - an underexpression of S100P.

[0554] According to a second variant, the reference value of each additional gene is determined from a reference biological sample from subjects suffering from a viral infection. Thus, it may be concluded that there is a bacterial infection when the comparison of the level of expression of the additional genes at the level of the mRNA transcripts with respect to the respective reference values ​​highlights at least one variation in expression chosen from:

[0555] - overexpression of PI3,

[0556] - overexpression of EBI3,

[0557] - overexpression of ADGRE1, and

[0558] - overexpression of S100P.

[0559] According to a particular embodiment, the method according to the invention comprises measuring the variation in the expression of all the target genes and the following additional genes: SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8, RSAD2, IFI27, OAS1, IFIT1, IFI44L, PI3, EBI3, ADGRE1 and S100P.

[0560] The conclusion as to the viral or bacterial nature of the infection is made as defined previously on the basis of the overexpression or underexpression of said genes according to the determined reference values.

[0561] Thus, according to a particular embodiment, the method comprises the steps:

[0562] - obtaining a biological sample of blood, preferably whole blood, from a subject with an infection,

[0563] - bringing said biological sample into contact with reagents specific for the expression products of one or more viral genes according to the present description, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and optionally of one or more additional genes chosen from PI3, EBI3, ADGRE1 and S100P,

[0564] - measurement of the expression of said target genes, and possibly of the additional gene(s).

[0565] According to a preferred embodiment, the method comprises the steps:

[0566] - obtaining a biological sample of blood, preferably whole blood, from a subject with an infection,

[0567] - bringing said biological sample into contact with reagents specific for the expression products of at least one viral target gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1, IFI44L, and at least one bacterial gene chosen from SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and optionally one or more additional genes chosen from PI3, EBI3, ADGRE1 and S100P,

[0568] - measurement of the expression of said target genes, and possibly of the additional gene(s).

[0569] Another subject of the invention relates to a kit for in vitro or ex vivo measurement of the expression of at least one viral target gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1, IFI44L, and at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, said kit comprising reagents specific for the expression products of said target genes. According to a particular embodiment, the kit comprises reagents specific for the expression products of at least three target genes, four target genes, five target genes, six target genes, seven target genes, eight target genes or all of the target genes.

[0570] In particular, the kit allows the implementation of the method according to the invention. The kit according to the invention can therefore be advantageously used for determining the viral or bacterial nature of an infection.

[0571] Consequently, all the particular and preferred embodiments described for the method according to the invention, in particular on the combinations of target genes whose expression is measured, also apply to the kit.

[0572] The specific reagents for measuring gene expression are known to those skilled in the art and according to a particular embodiment, these are amplification primers and / or hybridization probes.

[0573] Such reagents make it possible to quantitatively determine the level of transcripts of said selected gene in the test biological sample. As explained above, the level of transcripts determined may not correspond directly to the quantity of transcripts present in the biological sample, but may be a derived value representative of the quantity of transcripts. Indeed, in a conventional manner, the quantitative determination may include a step of amplification and / or normalization and / or calculation of a ratio...

[0574] By kit is meant a set of products and / or tools to be used together to obtain, in particular, the determination of the level of transcripts of the target genes defined within the scope of the invention. The necessary reagents may or may not be brought together within the same kit or the same device.

[0575] The term "amplification primer" or "primer" means a nucleotide fragment which may consist of 5 to 100 nucleotides, preferably 15 to 30 nucleotides, and which has a specificity for hybridization with a target nucleotide sequence, under conditions determined for the initiation of an enzymatic polymerization, for example in an enzymatic amplification reaction of the target nucleotide sequence. Generally, "primer pairs" are used, consisting of two primers. When it is desired to carry out the amplification of several different biomarkers (e.g. genes or mRNAs of said genes), several different primer pairs are preferably used, each preferably having a capacity to hybridize specifically with a different biomarker.

[0576] The person skilled in the art is fully capable, from the sequence of a gene, and in particular from the sequence of the corresponding transcripts, for example those listed in Table 2, of determining the nucleotide sequences of the primers in order to enable amplification of the transcripts.

[0577] According to a particular embodiment, primers are present in the kit, said primers comprising, or consisting of, a nucleotide sequence complementary to at least part of a sequence of the transcripts as presented in Table 2 above.

[0578] The term "probe" or "hybridization probe" means a nucleotide fragment typically consisting of 5 to 100 nucleotides, preferably 15 to 90 nucleotides, even more preferably 15 to 35 nucleotides, having a hybridization specificity under determined conditions to form a hybridization complex with a target nucleotide sequence. The probe also comprises a reporter (such as a fluorophore, an enzyme or any other detection system), which will allow the detection of the target nucleotide sequence. In the present invention, the target nucleotide sequence may be a nucleotide sequence included in a messenger RNA (mRNA) or a nucleotide sequence included in a complementary DNA (cDNA) obtained by reverse transcription of said mRNA. When it is desired to target several biomarkers (eggenes or mRNAs of said genes) different, several different probes are preferably used, each preferably having a capacity to hybridize specifically with a different biomarker.

[0579] By "hybridization" is meant the process during which, under appropriate conditions, two nucleotide fragments, such as for example a hybridization probe and a target nucleotide fragment, having sufficiently complementary sequences, are capable of forming a double strand with stable and specific hydrogen bonds.

[0580] A nucleotide fragment "capable of hybridizing" with a polynucleotide is a fragment capable of hybridizing with said polynucleotide under hybridization conditions, which can be determined in each case in a known manner. The hybridization conditions are determined by the stringency, that is to say the rigor of the operating conditions. The hybridization is all the more specific as it is carried out at a higher stringency.

[0581] Stringency is defined in particular as a function of the base composition of a probe / target duplex, as well as by the degree of mismatch between two nucleic acids. Stringency may also be a function of reaction parameters, such as the concentration and type of ionic species present in the hybridization solution, the nature and concentration of denaturing agents and / or the hybridization temperature. The stringency of the conditions under which a hybridization reaction is to be carried out will depend mainly on the hybridization probes used. All of these data are well known and the appropriate conditions can be determined by the person skilled in the art.

[0582] In general, depending on the length of the hybridization probes used, the temperature for the hybridization reaction is between about 20 and 70°C, in particular between 35 and 65°C in a saline solution at a concentration of about 0.5 to 1 M. A step of detecting the hybridization reaction is then carried out.

[0583] According to a preferred embodiment, the kit comprises a control sample calibrated to contain the quantity of transcripts of at least two target genes, and optionally one or more additional genes, corresponding to the quantity or concentration representative of the level of expression measured in a pool of samples from subjects presenting a bacterial infection and / or a control sample calibrated to contain the quantity of transcripts of at least two target genes, and optionally one or more additional genes, corresponding to the quantity or concentration representative of the level of expression measured in a pool of samples from subjects presenting a viral infection.

[0584] In other words, the control sample is calibrated to contain the average quantity of transcripts of said target genes obtained from a pool of samples from subjects with a bacterial infection or from subjects with a viral infection.

[0585] According to one embodiment, the reagents specific to the expression of the target genes, more precisely, amplification products and / or detection products, such as for example primers or probes, can be linked to the same solid support. The kit can therefore comprise a solid support comprising one or more oligonucleotide(s) suitable for determining the level of transcripts of the or each target gene, or even one or more oligonucleotide(s) suitable for determining the level of transcripts of the gene or each selected housekeeping gene, or even one or more oligonucleotide(s) suitable for detecting at least one target gene, as previously described. Such solid supports are well known to those skilled in the art, and in particular described in applications WO2008 / 140568 and WO2017 / 093672 to which reference may be made for further details.

[0586] The kit, in all its embodiments, may also further comprise reagents specific for the expression products of one or more additional genes selected from PI3, EBI3, ADGRE1 and S100P and combinations thereof.

[0587] The kit may also comprise, in the same manner as defined above, a value of the level of expression of the additional genes and / or control samples (positive or negative) of said additional genes.

[0588] The kit, in all its embodiments, may also further comprise reagents specific for the expression products of one or more housekeeping genes. Again, the kit according to the invention may comprise reagents specific for the expression products of each selected housekeeping gene.

[0589] According to a particular embodiment, the kit is in the form of a consumable integrating nucleic acid purification, multiplex nested PCR and detection in a single consumable in the form of a FilmArray® cassette or pouch. Such a consumable is advantageously intended for use with the BioFire® FilmArray® V2.0 and Torch systems.

[0590] Another subject matter relates to the use of a kit as defined above to determine the viral or bacterial nature of an infection in a subject.

[0591] Another subject of the present description relates to a method comprising the quantitative measurement, in particular by RT-qPCR, of the mRNAs of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and optionally of one or more additional genes as defined previously, in a biological blood sample from a subject presenting an infection.

[0592] The description also relates to methods for determining the viral or bacterial nature of an infection in an infected subject as defined above, which further comprise a step of treating the viral or bacterial infection.

[0593] According to a particular embodiment, when a viral infection is identified, the treatment comprises the administration of at least one antiviral agent. The person skilled in the art is able to choose the most suitable antiviral agent from among the known agents.A titre d’exemple, l’agent antiviral peut être choisi parmi les agents suivants : amantadine, rimantadine, ritonavir, cobicistat, interferon alfa-2b / ribavirin, ombitasvir / paritaprevir / ritonavir, peginterferon alfa-2a, peginterferon alfa-2b, maraviroc, raltegravir, dolutegravir, elvitegravir, sofosbuvir, enfuvirtide, foscamet, fomivirsen, zanamivir, oseltamivir, peramivir, nevirapine, etravirine, efavirenz, rilpivirine, delavirdine, nevirapine, daclatasvir, entacavir, lamivudine, adefovir, didanosine, tenofovir, abacavir, lamivudine, zidovudine, stavudine, emtricitabine, zalcitabine, telbivudine, didanosine, boceprevir, simeprevir, telaprevir, lopinavir, fosamprenavir, darunavir, ritonavir, tipranavir, atazanavir, nelfinavir, amprenavir, indinavir, saquinavir, ribavirin, valacyclovir, famciclovir, acyclovir, ganciclovir, valganciclovir et cidofovir.

[0594] According to a particular embodiment, when a viral infection is identified, the treatment comprises the administration of at least one antibiotic. The person skilled in the art is able to choose the most suitable antibiotic from among the known antibiotics. For example, the antibiotic may be chosen from the following antibiotics: erythromycin, clindamucin, gentamicin, tetracycline, amoxicillin, amikacin, aztreonam, chloramphenicol, ceftazidime, clindamycin, cefalotin, ciprofloxacin, colistin, cefotetan, cefotaxime, erythromycin, fusidic acid, fosfomycin, cefoxitin, furans, gentamicin, imipenem, kanamycin, lincomycin, cefamandole, minocycline, latamoxef, metronidazole, nalidixic acid, netilmicin, oxacillin, benzylpenicillin, pefloxacin, piperacillin, pristinamycin, rifampicin, spiramycin, sulfonamides, streptomycin, trimethoprim, sulfametoxazole, tetracycline, teicoplanin, ticarcillin, tobramycin, trimethoprim, vancomycin,meclocycline, sulfacetamide, ceftobiprole, ceftaroline, dalbavancin, daptomycin, linezolid, mupirocin, oritavancin, telavancin, vignecycline, vancomycin, aminoglycosides, carbapenems, ceftazidime, cefepime, ceftobiprole, fluorquinolones, piperacillin / tazobactam, ticarcillin / clavulanic acid, linezolid, streptogramins, daptomycin, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, spectinomycin, geldanamycin, herbimycin and rifaximin.

[0595] The present invention is illustrated in a non-limiting manner from the following examples.

[0596] EXAMPLES

[0597] 1. Materials and methods

[0598] 1.1 Clinical characteristics of patients & samples

[0599] Clinical whole blood samples were collected in PAXgene® tubes upon patient admission to the emergency department (ED) following the manufacturer's recommendations. A total of 191 samples were collected with the following distribution: 68 samples from a characterized bacterial infection and 123 samples from a characterized viral infection.

[0600] The origin and distribution of the samples are summarized below:

[0601] Patients: Female - 82 (42.9%); Male 109 (57.1%)

[0602] Average age: 3.4 years

[0603] Bacterial infection (GRAM-), n(%): 28 (14.6)

[0604] Bacterial infection (GRAM+), n(%): 24 (12.6)

[0605] Probable bacterial infection, n(%): 16 (8.4)

[0606] Viral infection, n(%): 123 (64.4)

[0607] 1.2. Identification and validation of biomarkers An initial selection of transcriptomic biomarkers characteristic of viral and bacterial infections was carried out via the Applicant's internal database. Several hundred biomarkers were thus identified.

[0608] For each of them, several scores were then assigned in order to evaluate a multitude of criteria, namely in particular the capacity for expression from RNAseq data from sample banks, the capacity to discriminate between a viral and bacterial infection from micro-array data from public databases, or the possibility of developing primer pairs for amplification in an automated PCR system (FilmArray® for example).

[0609] Taking into account the different scores obtained for each biomarker, an overall score was calculated to allow optimal selection and identification of the most promising biomarkers for identifying the nature of the infection.

[0610] Then, to finally validate the identified biomarkers, the patient samples were divided into two data groups. The first group, called the “TRAIN” set (n=128), is used to train the learning model on the data, while the second group, called the “TEST” set (n=63), is used for independent performance validation.

[0611] To assess the individual biomarker performance, the area under the ROC curve was calculated with a 95% confidence interval (95% CI). For the combination performance, analyses were performed using complex machine learning-based classifiers using R version 3.6.1.

[0612] Two methods in particular were used to assess the importance of variables. The first is the "explain" function of the FastShap package, which is derived from game theory. A reward (weight) is given to the biomarkers that contribute the most to the machine learning model to classify patients and allow the identification of the nature of the infection (viral or bacterial).

[0613] The second method is the "Featureimp" function from the IML package which returns the factor by which the model's prediction error increases when a feature is shuffled.

[0614] Ultimately, the selection made it possible to identify viral biomarkers, and in particular biomarkers involved in the interferon pathway and antigen presentation mediated by MHC class II, but also bacterial biomarkers, in particular the biomarkers SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

[0615] The performance was also evaluated and confirmed on two other machine learning models, namely Random Forest and Partial Least Squares-Discriminant (PLS) regression.

[0616] 2. Results

[0617] 2.1 BoxPlot

[0618] BoxPlot analysis reveals the overexpression / underexpression of different target genes depending on the nature of the infection. Thus, when comparing the expressions of target genes between viral and bacterial infections, we see that the genes SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP are overexpressed during a bacterial infection while the genes SIGLEC1, ISG15, HERC6, IFI44L, RSAD2, IFI27, OAS1 and IFIT1 are overexpressed during a viral infection.

[0619] 2.2 Analysis of the performance of the biomarkers according to the invention The performance of the target genes of the method according to the invention for determining the viral or bacterial nature of an infection is presented in the tables below. For each model, the performance was evaluated several times and the AUC of the model therefore corresponds to the average of the different AUCs obtained.

[0620] Performance obtained for the identification of the viral or bacterial nature of the infection based on 2-gene combinations: [Table 6]

[0621] Performance obtained for the identification of the viral or bacterial nature of the infection based on three-gene combinations:

[0622] [Table 7]

[0623]

[0624] Performance obtained for the identification of the viral or bacterial nature of the infection based on 4-gene combinations:

[0625] [Table 8]

[0626]

[0627]

[0628] Performance obtained for the identification of the viral or bacterial nature of the infection based on 5-gene combinations:

[0629] [Table 9]

[0630] Performance obtained for the identification of the viral or bacterial nature of the infection based on 6-gene combinations:

[0631] [Table 10]

[0632] Performance obtained for the identification of the viral or bacterial nature of the infection based on 7-gene combinations:

[0633] [Table 11]

[0634] Performance obtained for the identification of the viral or bacterial nature of the infection based on 8-gene combinations:

[0635] [Table 12]

[0636] Performance obtained for the identification of the viral or bacterial nature of the infection based on 9-gene combinations:

[0637] [Table 13]

[0638] Performance obtained for the identification of the viral or bacterial nature of the infection based on the 10 target gene combinations:

[0639] [Table 14]

[0640] Performance obtained for the identification of the viral or bacterial nature of the infection based on the combinations of 11 target genes:

[0641] [Table 15]

[0642] Performance obtained for the identification of the viral or bacterial nature of the infection based on the 12 target gene combinations:

[0643] [Table 16]

[0644] Performance obtained for the identification of the viral or bacterial nature of the infection based on the combinations of 13 target genes:

[0645] [Table 17]

[0646] Performance obtained for the identification of the viral or bacterial nature of the infection based on the combinations of the 14 target genes:

[0647] [Table 18]

[0648] Performance obtained for the identification of the viral or bacterial nature of the infection based on the combinations of the 14 target genes and the 4 additional genes:

[0649] [Table 19]

[0650] Thus, the transcriptomic signatures according to the invention make it possible to determine the viral or bacterial nature of an infection in an infected patient with a robust level of performance because the AUCs obtained on the TEST set are generally equal to or greater than the AUCs obtained on the TRAIN set. BIBLIOGRAPHICAL REFERENCES

[0651] Takeuchi O, Akira S (2010), “Pattern recognition receptors and inflammation”; Cell 140 (6):805-820.

[0652] Ramilo O, Mejias A (2009), “Shifting the paradigm: Host gene signatures for diagnosis of infectious diseases”; Cell Host Microbe 6(3): 199-200.

[0653] Fauci, A. S et al. (2014), “The perpetual challenge of antimicrobial resistance”; JAMA 311, 1853-1854.

[0654] Hu et al. (2013), “Gene expression profiles in febrile children with defined viral and bacterial infection”; PNAS 12792-12797, vol.110, no. 31.

[0655] Eric D. Brown et al. (2016), « Antibacterial drug discovery in the resistance era » - Review - doi : 10.1038 / naturel7042.

[0656] Ephraim L. Tsalik et al. (2021), « Discriminating bacterial and viral infection using a rapid host gene expression test”; Critical Care Medecine - Vol 49, no. 10.

[0657] Mark A. Poritz et al. (2011), « FilmArray, an automated Nested Multiplex PCR System for Multi-Pathogen Detection: development and application to respiratory tract infection”, PLoS ONE 6(10):e26047.

[0658] William M. Schneider et al. (2014), “Interferon-stimulated genes: a complex web of host response” Annu Rev Immunol. 2014 ; 32: 513-545. doi:10.1146 / annurev-immunol-032713-120231.

[0659] Emily Yang et al. (2020), « All about the RNA : interferon-stimulated genes that interfere with viral RNA processes”; Front. Immunol. 11:605024.

[0660] Trine H. Mogensen et al. (2001), « Molecular pathways in virus-induced cytokine production”; Microbiology and molecular biology review, Mar. 2001, p.131-150.

[0661] Kawasaki et al. (2014), « Toll-like receptor signaling pathway » ; Front. Immunol., Sec. Cancer Immunity and Immunotherapy.

[0662] Hochrainer et al. (2005), « The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects » ; Genomics 85 153-164

Claims

Claims 1. In vitro or ex vivo method for determining the viral or bacterial nature of an infection from a biological sample of an infected subject, or subject likely to be infected, comprising the following steps: (a) measurement of the expression of at least one viral target gene and at least one bacterial target gene selected from the bacterial target genes OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2. (b) comparing the expressions measured in step (a) with predetermined reference expression values ​​of said target genes, and (c) conclusion as to the viral or bacterial nature of the infection based on the comparison results.

2. Method according to claim 1, characterized in that the viral target gene is chosen from the viral target genes of the interferon pathway, the pro-inflammatory cytokine pathway, the Toll-like receptor signaling pathway, the RIG-I-like receptor signaling pathway and the MHC class II-mediated antigen presentation pathway.

3. Method according to claim 1 or 2, characterized in that the viral target gene is chosen from the viral target genes involved in the interferon pathway and antigen presentation mediated by MHC class II.

4. Method according to claim 3, characterized in that the viral target genes are chosen from IFI27, SIGLEC1, IFN-a, IFN-P, IFN-e, IFN-K, IFN-CÛ, IFN-y, IFNL1, IFNL2, IFNL3, ADAR1, IFIT1, IFIT2, IFIT3, IFIT5, IFI44L, ISG15, ISG20, MDA5, OAS1, OAS2, OAS3, OASL, PARP12, PKR, RIG-I, RNaseL, RSAD2, RBBP6, SHFL, TRIM22, TRIM25, TRIM32, TRIM69, Viperin, ZAP, ZCCHC3, ZNFX1, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6 and combinations thereof.

5. Method according to one of claims 1 to 4, characterized in that step (a) comprises or consists of the measurement of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L and at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2.

6. Method according to claim 5, characterized in that step (a) comprises measuring the expression of the viral target gene IFI27 and the bacterial target gene OLAH.

7. Method according to claim 6, characterized in that step (a) also comprises measuring the expression of the bacterial target gene FAM20A.

8. Method according to one of claims 1 to 5, characterized in that the measurement step (a) comprises or consists of measuring the expression of two viral target genes chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L and two bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH, FAM20A, IL1R2 and MMP8.

9. Method according to one of claims 1 to 5, characterized in that the measurement step (a) comprises or consists of measuring the expression of two to five viral target genes chosen from SIGLEC1, ISG15, HERC6, RSAD2, IFI27, OAS1, IFIT1 and IFI44L and three or four bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH, FAM20A, IL1R2 and MMP8.

10. Method according to claim 5, characterized in that the measurement step (a) comprises or consists of measuring the expression of the viral target gene IFI27, and optionally of at least one other viral gene chosen from SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L, and of at least two bacterial target genes chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, and preferably chosen from OLAH, FAM20A, IL1R2 and MMP8.

11. Method according to claim 5, characterized in that step (a) comprises or consists of the measurement of at least one viral target gene chosen from SIGLEC1, ISG15 and HERC6, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from IL1R2, OLAH and FAM20A.

12. Method according to claim 5, characterized in that step (a) comprises or consists of the measurement of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, of the bacterial target gene OLAH, and of at least one other bacterial target gene chosen from FAM20A, IL1R2, MMP8, RETN and SLC1A2, preferably from FAM20A, IL1R2 and MMP8.

13. Method according to claim 5, characterized in that step (a) comprises or consists of the measurement of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1 and IFI44L, of the bacterial target gene FAM20A, and of at least one other bacterial target gene chosen from OLAH, IL1R2, MMP8, RETN and SLC1A2, preferably from OLAH, IL1R2 and MMP8.

14. Method according to claim 5, characterized in that the measuring step (a) comprises or consists of measuring the expression of the viral target gene IFI27, of another viral target gene chosen from HERC6, SIGLEC1, IFI44L and ISG15, of the bacterial target gene FAM20A and of another bacterial target gene chosen from OLAH and IL1R2.

15. Method according to claim 9, characterized in that step (a) comprises or consists of measuring the expression of the viral target gene IFI27, of two other viral target genes chosen from SIGLEC1, HERC6, OAS1 and IFIT1, of the bacterial target gene FAM20A and of another bacterial target gene chosen from OLAH, IL1R2 and MMP8.

16. Method according to claim 5, characterized in that the measuring step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, of another viral target gene chosen from IFIT1, HERC6, ISG15 and ISG15, of the bacterial target genes FAM20A and MMP8, and of another bacterial target gene chosen from OLAH and ILlR2.

17. Method according to claim 5, characterized in that the measurement step (a) comprises or consists of measuring the expression of the viral target genes IFI27 and SIGLEC1, and of two other viral target genes chosen from IFIT1, OAS1, HERC6 and ISG15, of the bacterial target genes FAM20A and MMP8, and of another bacterial target gene chosen from OLAH and IL1R2.

18. Method according to claim 1, characterized in that step (a) consists of measuring a combination of viral and bacterial target genes chosen from the combinations of target genes listed in tables 6 to 12 and which have an AUC of the model for determining the viral or bacterial nature of the infection of at least 0.

90.

19. Method according to one of claims 5 to 18, characterized in that the predetermined reference expression value of the target genes corresponds to the respective expression of said target genes in a reference biological sample obtained from a subject having a bacterial infection and in that it is concluded that there is an infection of viral nature when the results of the comparison of the expression of the target genes highlight at least one variation of expression chosen from: - overexpression of SIGLEC1, - overexpression of ISG15, - overexpression of HERC6, - overexpression of RSAD2, - overexpression of IFI27, - overexpression of OAS1, - overexpression of IFIT1, and - an overexpression of IFI44L, and at least one other expression variation chosen from: - underexpression of SLC1A2, - an underexpression of IL1R2, - underexpression of FAM20A, - a sub-expression of OLAH, - an underexpression of RETN, and - an underexpression of MMP8.

20. Method according to one of claims 5 to 18, characterized in that the predetermined reference expression value of said target genes corresponds to the respective expression of said target genes in a reference biological sample obtained from a subject having a viral infection and in that it is concluded that there is an infection of a bacterial nature when the results of comparison of expression of the target genes highlight at least one variation of expression chosen from: - an underexpression of SIGLEC1, - an underexpression of ISG15, - underexpression of HERC6, - an underexpression of RSAD2, - a sub-expression of IFI27, - an underexpression of OAS1, - an underexpression of IFIT1, and - a sub-expression of IFI44L, and at least one other expression variation chosen from: - overexpression of SLC1A2, - overexpression of IL1R2, - overexpression of FAM20A, - an overexpression of OLAH, - overexpression of RETN, and - overexpression of MMP8 21. Method according to one of claims 1 to 20, characterized in that it further comprises a step (a') of measuring the expression of at least one additional target gene chosen from PI3, EBI3, ADGRE1 and S100P, a step (b') of comparing the expressions measured in step (a') with reference expression values ​​of said additional target genes.

22. Method according to one of claims 1 to 21, characterized in that the measurement of the expression of the target genes is carried out at the mRNA level.

23. Method according to one of claims 1 to 22, characterized in that the measurement of the variation in expression is carried out by amplification via RT-PCR, preferably quantitative RT-PCR, or nested PCR.

24. Method according to one of claims 1 to 23, characterized in that the expression is normalized relative to the expression of one or more housekeeping genes, preferably chosen from DECRI, HPRT1, PPIB, GAPDH, and ACTB.

25. Method according to one of claims 1 to 24, characterized in that the biological sample comes from a subject who is a child, preferably a child under 4 years old, and more preferably a child under 2 years old.

26. Method according to one of claims 1 to 25, characterized in that the biological sample is a blood sample, preferably a whole blood sample.

27. Kit for in vitro or ex vivo measurement in a biological sample of gene expression, said kit comprising means for determining the variation in the level of expression of at least one viral target gene chosen from IFI27, SIGLEC1, ISG15, HERC6, RSAD2, OAS1, IFIT1, IFI44L, and of at least one bacterial target gene chosen from OLAH, FAM20A, IL1R2, MMP8, RETN and SLC1A2, said means preferably being primers or probes.

28. Use of the kit according to claim 27 for determining the viral or bacterial nature of an infection from a biological sample of a subject.

Images