FR3138815A1 - Determining the viral or bacterial nature of an infection - Google Patents

Abstract

The subject of the present invention is in vitro or ex vivo methods and kits for determining from a biological sample of a subject the nature of an infection, namely viral or bacterial, through identification variation in the expression level of several biomarkers. In particular, the method comprising the steps of (a) measuring the expression of at least two genes chosen from the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, of (b) comparison of the expressions measured in step (a) with reference expression values of said target genes, and (c) conclusion as to the viral or bacterial nature of the infection on the basis of the comparison results.

Description

Determining the viral or bacterial nature of an infection

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

Viruses and bacteria interact with different recognition receptors on the surface of leukocytes present in circulating blood. This interaction leads to 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.

In this context, analysis of the host transcriptomic profile can provide an indirect approach to detecting the nature of an infection, thus complementing direct approaches, such as culture or nucleic acid amplification (Ramilo et al. 2009). This is also of particular interest because viral infections are frequently the cause of fever with no apparent source, especially in young children.

Furthermore, considering the common practice in hospitals to systematically administer, as a preventive measure, antibiotics to febrile patients until culture test results are obtained unfortunately implies that many viral infections are wrongly treated with drugs. antimicrobials.

Furthermore, excessive administration of antibiotics has been shown to lead to an increase in bacterial resistance, not only at the individual level but also at a more global level. Consequently, the misuse and overuse of available antibiotics actively contribute to the development of antimicrobial resistance (Fauci et al. 2014). Furthermore, due to difficulties in distinguishing viral, bacterial, or noninfectious etiologies, a number of patients are inappropriately treated with antibiotics at high rates.

An early distinction between patients with a viral infection and those with a bacterial infection could therefore allow more precise and refined management of said patients, while significantly reducing the unnecessary use of antibiotics.

In recent years, there has been growing interest in the discovery of biomarkers capable of distinguishing, based on whole blood gene expression, viral infections from bacterial infections presenting similar initial clinical phenotypes. 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).

Increasing efforts are therefore being made to develop host biomarkers to distinguish viral infections from bacterial infections, particularly in febrile children (D. Brown et al. 2016).

This interest arises not only from the need to distinguish life-threatening bacterial infections from viral infections, but also to avoid unnecessary prescription of empiric antibiotic therapy, regardless of the severity of the infection. As previously mentioned, the overconsumption 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. .

For example, document WO2018011316 describes a method for identifying a subject with a bacterial infection. In particular, the method consists of 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.

However, additional efforts are needed to evaluate the accuracy and diagnostic utility of biomarkers, particularly transcriptomic ones, before they can be transformed into a clinically applicable test to determine the viral or bacterial origin of an infection.

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

Summary

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.

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 expression level of at least two, three, four, five, six, seven, eight or nine target genes chosen from the following target genes: SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8.

The method according to the invention, from a biological sample from a subject infected or likely to be infected, thus comprises the following steps:
(a) measurement of the expression of at least two genes chosen from the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8,
(b) comparison of 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.

The advantages of the method according to the invention are numerous, in particular:
(i) accurately differentiate the viral or bacterial nature of the infection with a high level of performance, the majority of combinations having an AUC of at least 0.80.
(ii) quickly identify significant variations in the level of expression of genes, in particular by the implementation of automated systems or via detection kits according to the invention,
(iii) avoid the identification of false positives corresponding to the presence of non-pathogenic bacteria or viruses naturally present in subjects,
(iv) allow a diagnosis 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.

It is thus to the merit of the inventors to 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 of this expression to identify the source of the infection. . Identifying the nature of the infection makes it possible to support the clinician in providing appropriate and personalized care, in particular to avoid the unnecessary prescription of antibiotics when the infection is viral in nature.

Preferably, measurement step (a) comprises or consists of measuring at least one target gene chosen from SIGLEC1, ISG15 and HERC6, and at least one other target gene chosen from SLC1A2, IL1R2, OLAH, FAM20A , RETN and MMP8.

Preferably, step (a) comprises or consists of measuring the expression of the target gene SIGLEC1 and at least one other target gene chosen from ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from IL1R2, OLAH and FAM20A.

Preferably, step (a) comprises or consists of measuring the expression of the target gene HERC6 and at least one other target gene chosen from SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

Preferably, 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 ; OLAH_MMP8 ; OLAH_RETN; ISG15_HERC6 ; IL1R2_MMP8 ; IL1R2_RETN ; ISG15_MMP8 and ISG15_SLC1A2, and preferably chosen from the following gene combinations: SIGLEC1_IL1R2; SIGLEC1_FAM20A ; HERC6_IL1R2; SIGLEC1_OLAH and HERC6_OLAH.

Preferably, step (a) comprises or consists of measuring at least one target gene chosen from SIGLEC1, ISG15 and HERC6, and at least two target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN and MMP8, and preferably IL1R2, OLAH and FAM20A.

Preferably, step (a) comprises or consists of measuring the expression of the target genes SIGLEC1 and 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.

Preferably, step (a) comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A, SIGLEC1_SLC1A2_OLAH, SIGLEC1_HERC6_IL1R2, SIGLEC1_FAM20A_OLAH, SIGLEC1_IL1R2_MMP8, SIGLEC1 _ISG15_IL1R2, SIGLEC1_SLC1A2_IL1R2, SIGLEC1_IL1R2_OLAH, SIGLEC1_SLC1A2_FAM20A and HERC6_FAM20A_OLAH, and more preferably from SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A and SIGLEC1_SLC1A2_OLAH.

Preferably, step (a) comprises or consists of measuring at least two target genes chosen from SIGLEC1, ISG15 and HERC6, and at least two target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, and preferably IL1R2, OLAH and FAM20A.

Preferably, step (a) comprises or consists of measuring the expression of the target gene SIGLEC1 and at least three target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN.

Preferably, step (a) comprises or consists of measuring the expression of a combination of four target genes chosen from the following combinations: SIGLEC1_IL1R2_FAM20A_MMP8, SIGLEC1_HERC6_IL1R2_FAM20A, SIGLEC1_ISG15_IL1R2_FAM20A, SIGLEC1_IL1R2_FAM20A_OLAH, SIGLEC1_IL1R2_ FAM20A_RETN, SIGLEC1_SLC1A2_IL1R2_FAM20A, SIGLEC1_SLC1A2_FAM20A_OLAH, ISG15_HERC6_IL1R2_FAM20A, SIGLEC1_FAM20A_OLAH_MMP8 , and HERC6_IL1R2_FAM20A_OLAH.

Preferably, step (a) 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.

Preferably, step (a) 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, SLC1A2, OLAH, FAM20A, RETN and IL1R2, preferably from OLAH, SLC1A2, FAM20A and IL1R2.

Preferably, step (a) comprises measuring the expression of a combination of five target genes chosen from the following combinations:
- SIGLEC1_HERC6_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_OLAH_MMP8
- SIGLEC1_ISG15_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_RETN_MMP8
- SIGLEC1_SLC1A2_IL1R2_FAM20A_MMP8
- SIGLEC1_ISG15_HERC6_IL1R2_FAM20A
- SIGLEC1_HERC6_IL1R2_FAM20A_OLAH
- SIGLEC1_SLC1A2_FAM20A_OLAH_MMP8, and
- SIGLEC1_ISG15_IL1R2_FAM20A_OLAH.

Preferably, step (a) comprises or consists of measuring the expression of the target genes SIGLEC1 and MMP8, and at least four other target genes chosen from HERC6, ISG15, IL1R2, SLC1A2, OLAH, FAM20A and RETN .

Preferably, step (a) comprises or consists of measuring the expression of target genes SIGLEC1, FAM20A and MMP8 and at least three other target genes chosen from ISG15, HERC6, IL1R2, SLC1A2, OLAH, and RETN.

Preferably, step (a) comprises or consists of measuring the expression of target genes SIGLEC1, ISG15 and SLC1A2, and at least three other target genes chosen from HERC6, IL1R2, OLAH, FAM20A, MMP8 and RETN.

Preferably step (a) comprises measuring the expression of a combination of six target genes chosen from the following combinations:
- SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_MMP8 ;
- SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
- SIGLEC1_ISG15_IL1R2_FAM20A_RETN_MMP8 ; And
- SIGLEC1_IL1R2_FAM20A_OLAH_RETN_MMP8.

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 can be concluded that an infection is of a viral nature when the results of comparison of expression of the target genes highlight at least two variations chosen from the following variations:
- overexpression of SIGLEC1,
- overexpression of ISG15,
- overexpression of HERC6,
- an underexpression of SLC1A2,
- an underexpression of IL1R2,
- a subexpression of FAM20A,
- a subexpression of OLAH,
- a subexpression of RETN, and
- an underexpression of MMP8.

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 an infection is of a bacterial nature when the results of comparison of expression of the target genes highlight at least two variations chosen from the following variations:
- a subexpression of SIGLEC1,
- a subexpression of ISG15,
- a subexpression of HERC6,
- overexpression of SLC1A2,
- overexpression of IL1R2,
- overexpression of FAM20A,
- an overexpression of OLAH,
- overexpression of RETN, and
- overexpression of MMP8.

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 RSAD2, IFI27, OAS1, IFIT1, IFI44L, 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') of conclusion as to the viral or bacterial nature of infection based on the results comparisons.

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

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

Preferably, in the method according to the invention, the expression is normalized relative to the expression of one or more housekeeping genes chosen from DECR1, HPRT1, PPIB, GAPDH, and ACTB.

Preferably, in the method according to the invention the subject is a child, preferably a child under 4 years old, and even more preferably, a child under 4 years old.

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

The invention also relates to a kit for measuring in vitro or ex vivo the expression of at least two target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, 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.

Brief description of the figures Fig. 1

represents the box plots of the expression of the target genes obtained from the raw RT-PCR values normalized with the housekeeping genes DECR1, HPRT1 and PPIB; A: Bacterial infection (n=68); B: Viral infection (n=123).

Detailed description of the embodiments

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, of a 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.

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

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 identified that the demonstration, from a biological sample of an infected subject or likely to be infected, of the variation in the level of expression of several target genes made it possible to characterize the viral nature or bacterial infection.

Thus, the method according to the invention comprises the following steps of:
(a) measurement, from the biological sample of an infected subject, of the expression of at least two target genes chosen from the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8,
(b) comparison of 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 of said subject based on the comparison results.

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 carried out by any method known to those skilled in the art allowing such a conclusion to be reached. The diagnosis can thus be made by a molecular method, such as for example a protein assay of procalcitonin (PCT), or directly by the clinician on the basis of symptom(s) or clinical sign(s) of the subject.

The clinical symptoms or signs associated with the presence of an infection are also well known to those 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, body temperature below 35.5°C, a respiratory symptom chosen from the group including cough, expectoration, dyspnea, tachypnea and pleuritic pain; a finding on auscultation, nausea with or without vomiting, systolic blood pressure greater than 90 mmHg, heart rate greater than 120 beats/min, a symptom of infection of an organ or organ system selected from the group consisting of respiratory tract infections, digestive tract infections, vaginal infections, meningitis, septicemia, erysipelas, peritonitis, cholangitis, cholecystitis and osteomyelitis.

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

The expression "nature of the infection" refers only to the etiology of said infection, namely an infection of a viral nature or an infection of a bacterial nature. The method according to the invention thus makes it possible to distinguish a viral infection from a bacterial infection, or vice versa.

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 health professional, in particular a doctor, a medical structure or a health establishment.

According to a 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 any particularly, a patient in the emergency department.

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

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 merit 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.

The chromosomal positions of the target genes according to the present invention are given in Table 1 below:

Embarrassed Chromosomal location (GRCh38/hg38) English Name SIGLEC1 Chr20: 3,686,970-3,712,600 Sialic Acid Binding Ig Like Lectin 1 ISG15 Chr1: 1,001,138-1,014,540 ISG15 Ubiquitin Like Edit HERC6 Chr4: 88378739-88443097 HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 6 SLC1A2 Chr11: 35251205-35420063 Solute Carrier Family 1 Member 2 IL1R2 Chr2: 101991960-102028544 Interleukin 1 Receptor Type 2 FAM20A Chr17:68535113-68601367 Golgi Associated Secretory Pathway Pseudokinase OLAH Chr10: 15032227-15073853 Oleoyl-ACP Hydrolase RETN Chr19:7669049-7670455 Resistin MMP8 Chr11: 102711796-102727050 Matrix Metallopeptidase 8

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.

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 target proteins conjugated to intermediate filaments, intercellular signaling, and antiviral activity during viral infections.

The HERC6 gene belongs to the HERC family of ubiquitin ligases, all of which contain at least a HECT domain of 350 amino acids catalyzing the formation of a thioester with ubiquitin before transferring it to a substrate.

The SLC1A2 gene encodes a member of a family of solute transporter 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.

The IL1R2 gene encodes a cytokine receptor protein that belongs to the interleukin 1 receptor family. This protein binds interleukin alpha (IL1A), interleukin beta (IL1B), and the interleukin 1 receptor of type I (IL1R1/IL1RA), 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 2q12. Alternative splicing gives rise to multiple transcript variants and membrane and soluble protein isoforms.

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.

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 process of medium-chain fatty acids.

The RETN gene codes for a protein with an antimicrobial role in the skin via antibacterial activity against Gram-positive and Gram-negative bacteria.

The MMP8 gene encodes a member of the matrix metalloproteinase (MMP) family of proteins. 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 gives rise to several active forms of the enzyme with distinct N-termini. This protein functions in the degradation of type I, II and III collagens.

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, the transcripts can therefore be defined as biomarkers.

By “biomarker” or “marker” is meant an objectively measurable biological characteristic which represents an indicator of normal or pathological biological processes following an infection.

The transcripts of the target genes according to the present invention are also known to those skilled in the art and their sequences are made available in the NCBI or Ensembl databases. Examples are presented in Table 2 below:

Embarrassed Reference Transcribed (NCBI database) SIGLEC1 NM_023068.4
NM_001367089.1 ISG15 NM_005101.4 HERC6 NM_017912.4
NM_001165136.2 SLC1A2 NM_004171.4
NM_001195728.3
NM_001252652.2 IL1R2 NM_004633.4
NM_001261419.2 FAM20A NM_017565.4
NM_001243746.2 OLAH NM_001039702.3
NM_018324.3 RETN NM_020415.4
NM_001385725.1
NM_001385726.1
NM_001385727.1
NM_001193374.2 MMP8 NM_002424.3
NM_001304442.2
NM_001304441.2

According to a preferred embodiment, the measurement of the expression of 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.

Any method known to those skilled in the art making it possible to measure the level of gene expression, or a variation of gene expression, at the transcriptional level can be used in the context of the method according to the invention.

Thus, the measurement can be carried out via a direct method making it possible to determine the presence of said transcript in the biological sample, or by indirect detection of the transcript after transformation of the latter into DNA.

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. By way of example, we will cite DNA chips, CAGE, SAGE and, more recently, high-throughput RNA sequencing called RNA-Seq.

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 via in particular a Reverse Transcription-Polymerase Chain Reaction or RT-PCR, by sequencing (preferably by high-throughput sequencing) or by hybridization techniques (for example with hybridization microchips or by techniques such as NanoString® nCounter®). All these methods are also well known to those skilled in the art and it is not necessary to detail them here.

According to a particular embodiment, the determination of gene expression can be carried out in the following manner:
(1) extraction of total RNAs from a blood sample or PBMCs and carrying out a reverse transcription step in order to obtain the different DNAs complementary to the different messenger RNAs initially present in the sample or the PBMCs (or cDNA),
(2) specific amplification of cDNAs. In this case, the specific reagent used comprises at least one gene-specific amplification primer. This step can be carried out by a PCR type amplification reaction or by any other appropriate amplification technique,
(3) determination of gene expression by quantifying cDNAs.

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 also called “Nested” PCR, for example using FilmArray technology. ® (Poritz et al. 2011) or the Biomark™ platform from Fluidigm. According to this embodiment, the expression is measured at the level of the mRNA transcripts of the target genes.

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 additional target genes defined later in the description, to determine their levels. respective expressions. Indeed, many tools are available, for example Geneious or Primer 3, said sequences can then be adjusted if necessary by the person skilled in the art.

Measuring the expression level makes it possible to determine the quantity of transcripts in the biological sample or also to give a derived value.

According to a particular embodiment, the expression level 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.

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: DECR1 (chromosomal location: chr8, 90001352-90053633), HPRT1 (chromosomal location: chrX, 134452842-134520513) and PPIB (chromosomal location: chr15:64155812 -64163205), RPLP0 (chromosomal location: chr12, 120196699-120201111), PPIA (chromosomal location: chr7, 44795960-44803117), GLYR1 (chromosomal location: chr16, 4803203-4847288), RANBP3 (chromosomal location: osomic: chr19, 5916139-5978140 ), B2M (chromosomal location: chr15, 44711492-44718145), TBP (chromosomal location: chr6, 170554369-170572859), GAPDH (chromosomal location: chr12, 6534517-6538371) and ACTB (chromosomal location: chr14, 552714 8-5530601). Chromosomal locations are given according to GRCh38/hg38. Preferably, the expression is normalized using one or more housekeeping genes chosen from: DECR1, HPRT1, PPIB, GAPDH, ACTB and their combinations, more preferably, chosen from DECR1, HPRT1, PPIB and their combinations.

In such a case, the reference level used is also standardized beforehand, in the same way. The normalization, whether for the reference level or for the level of transcripts of the biological sample to be tested, is carried out before the comparison, in particular before the calculation of a ratio between the level of transcripts of 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.

In the case where the level of transcript(s) of the genes is normalized 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 gene(s). of household used for standardization.

In general, 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 at 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.

For a given target gene, the reference expression value corresponds to an expression level of transcripts of said gene obtained from a reference biological sample from a subject having an infection of a specific nature. The biological reference 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 the determination of the expression level 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 a infection.

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.

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 biological reference sample from a subject having a bacterial infection.

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.

The comparison can be carried out by any methods known to those skilled in the art and can for example involve the calculation of a ratio or a difference. Advantageously, within the framework of the present method, the comparison(s) and the issuance of a conclusion as to the nature of the infection in the subject from which the biological sample comes, is carried out by a technique automated, computer-generated or computer-assisted.

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 of said level of expression. 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 level of expression of the target genes must be compared. The implementation examples present one of the possible methods.

According to a first variant embodiment of the invention, the reference expression value of each target gene is determined from a reference biological sample from subjects suffering from a bacterial infection. Thus, it can be concluded that an infection is of a viral nature when the comparison of the level of expression of the target genes at the level of the mRNA transcripts compared to the respective reference values, highlights at least two variations of expressions chosen from:
- overexpression of SIGLEC1,
- overexpression of ISG15,
- overexpression of HERC6,
- an underexpression of SLC1A2,
- an underexpression of IL1R2,
- a subexpression of FAM20A,
- a subexpression of OLAH,
- a subexpression of RETN, and
- an underexpression of MMP8.

According to a second alternative embodiment of the invention, the reference value of each target gene is determined from a biological reference sample from subjects suffering from a viral infection. Thus, it can be concluded that an infection is of a bacterial nature when the comparison of the level of expression of the target genes at the level of the mRNA transcripts compared to the respective reference values, highlights at least two variations of expressions chosen from:
- a SIGLEC1 subexpression,
- an ISG15 subexpression,
- a HERC6 subexpression,
- overexpression of SLC1A2,
- overexpression of IL1R2,
- overexpression of FAM20A,
- an overexpression of OLAH,
- overexpression of RETN, and
- overexpression of MMP8.

The person skilled in the art is able to opt for one or the other of the variants depending on the biological reference samples available.

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

According to a particular embodiment, the measurement step comprises or consists of measuring the expression of at least two target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A and RETN, and preferably chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH and FAM20A.

According to a particular embodiment, the measurement step comprises or consists of measuring the expression of three, four, five, six or seven target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, MMP8 and RETN, and preferably chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH and FAM20A.

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

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene SIGLEC1 and at least one other target gene chosen from ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene ISG15 and at least one other target gene chosen from SIGLEC1, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene HERC6 and at least one other target gene chosen from SIGLEC1, ISG15, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from SLC1A2, IL1R2, OLAH and FAM20A.

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of a combination of two target genes chosen from the following gene 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 ; OLAH_MMP8 ; OLAH_RETN; ISG15_HERC6 ; IL1R2_MMP8 ; IL1R2_RETN ; ISG15_MMP8 and ISG15_SLC1A2, and preferably chosen from the following gene combinations: SIGLEC1_IL1R2; SIGLEC1_FAM20A ; HERC6_IL1R2; SIGLEC1_OLAH and HERC6_OLAH. According to another particular embodiment, the measurement step comprises or consists of measuring the expression of at least three target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

According to a variant of this particular embodiment, the measurement step comprises or consists of measuring at least one target gene chosen from SIGLEC1, ISG15 and HERC6, and at least two target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN and MMP8, and preferably IL1R2, OLAH and FAM20A.

According to a variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene SIGLEC1 and at least two other target genes chosen from the group consisting of OLAH SLC1A2, IL1R2, FAM20A , RETN and MMP8.

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene HERC6 and at least two other target genes chosen from the group consisting of OLAH SLC1A2, IL1R2, FAM20A, RETN and MMP8.

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of the target gene ISG15 and at least two other target genes chosen from the group consisting of OLAH SLC1A2, IL1R2, FAM20A, RETN and MMP8.

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

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of the target genes SIGLEC1 and 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.

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

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

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations: SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A, SIGLEC1_SLC1A2_OLAH, SIGLEC1_HERC6_IL1R2, SIGLEC1_FAM20A_OLAH, SIGLEC1_IL1R2_MMP8, SIGLEC1_ISG15_IL1R2, SIGLEC1_SLC1A2_IL1R2, SIGLEC1_IL1R2_OLAH, SIGLEC1_SLC1A2_FAM20A, HERC6_FAM20A_OLAH, SIGLEC1_FAM20A_RETN, SIGLEC1_HERC6_FAM20A, SIGLEC1_FAM 20A_MMP8, SIGLEC1_IL1R2_RETN, ISG15_IL1R2_FAM20A, SIGLEC1_ISG15_FAM20A, ISG15_HERC6_IL1R2, HERC6_IL1R2_OLAH, SIGLEC1_HERC6_OLAH, HERC6_SLC1A2_OLAH, HERC6_IL1R2_RETN, HERC6_IL1R2_ MMP8, SIGLEC1_OLAH_MMP8, SIGLEC1_ISG15_OLAH, SIGLEC1_OLAH_RETN, HERC6_SLC1A2_IL1R2, ISG15_SLC1A2_OLAH, HERC6_FAM20A_RETN, HERC6_OLAH_RETN, ISG15_SLC1A2_IL1R2, HERC6_OLAH_MMP8, SIGLEC1_HERC6_RETN, ISG15_IL1R2_OLAH, ISG15_HERC6_OLAH, SIGLEC1_SLC1A2_RETN, ISG15_IL1R2_RETN, ISG15_FAM20A_OLAH, ISG15_IL1R2_MMP8, SIGLEC1_ SLC1A2_MMP8, ISG15_HERC6_RETN, SIGLEC1_ISG15_RETN, HERC6_SLC1A2_FAM20A, ISG15_HERC6_FAM20A, HERC6_FAM20A_MMP8, SLC1A2_FAM20A_OLAH, SIGLEC1_RETN_MMP8, HERC6_SLC1A2_RETN, SIGLEC1_ HERC6_SLC1A2, SLC1A2_IL1R2_OLAH, SIGLEC1_HERC6_MMP8, ISG15_OLAH_RETN, SIGLEC1_ISG15_SLC1A2, ISG15_OLAH_MMP8, SLC1A2_OLAH_MMP8, SLC1A2_OLAH_RETN, HERC6_RETN_MMP8, HERC6_SLC1A2_MMP8, SIGLEC1_ISG15_MMP8, IL1R2_FAM20A_OLAH, ISG15_HERC6_MMP8, ISG15_SLC1A2_FAM20A, ISG15_FAM20A_RETN, IL1R2_OLAH_MMP8, SLC1 A2_IL1R2_FAM20A, IL1R2_OLAH_RETN, SIGLEC1_ISG15_HERC6, FAM20A_OLAH_MMP8, ISG15_SLC1A2_RETN, IL1R2_FAM20A_MMP8, ISG15_HERC6_SLC1A2, ISG15_SLC1A2_MMP8, ISG15_FAM20A_MMP8 , IL1R2_FAM20A_RETN, SLC1A2_IL1R2_RETN, FAM20A_OLAH_RETN, OLAH_RETN_MMP8, SLC1A2_IL1R2_MMP8, ISG15_RETN_MMP8, IL1R2_RETN_MMP8, SLC1A2_FAM20A_RETN, SLC1A2_FAM20A_MMP8, SLC1A2_RETN_MMP8, and FAM20A_RETN_MMP8.

Preferably, according to this variant, the measurement step comprises or consists of measuring the expression of a combination of three target genes chosen from the following combinations: SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A, SIGLEC1_SLC1A2_OLAH, SIGLEC1_HERC6_IL1R2, SIGLEC1_FAM20A_OLAH, SIGLEC1_IL1R2_MMP8 , SIGLEC1_ISG15_IL1R2, SIGLEC1_SLC1A2_IL1R2, SIGLEC1_IL1R2_OLAH, SIGLEC1_SLC1A2_FAM20A and HERC6_FAM20A_OLAH, and more preferably from SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A and SIGLEC1_SLC1A2_OLAH.

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

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

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring SIGLEC1 and at least three target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN

According to another variant of this particular embodiment, the measurement 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, SLC1A2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, OLAH and FAM20A.

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

According to another variant of this particular embodiment, the measurement 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.

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

Preferred Combinations of 4 Genes SIGLEC1_IL1R2_FAM20A_MMP8 ISG15_HERC6_SLC1A2_IL1R2 SIGLEC1_HERC6_IL1R2_FAM20A HERC6_SLC1A2_OLAH_RETN SIGLEC1_ISG15_IL1R2_FAM20A ISG15_SLC1A2_IL1R2_OLAH SIGLEC1_IL1R2_FAM20A_OLAH HERC6_IL1R2_OLAH_RETN SIGLEC1_IL1R2_FAM20A_RETN HERC6_IL1R2_OLAH_MMP8 SIGLEC1_SLC1A2_IL1R2_FAM20A HERC6_IL1R2_RETN_MMP8 SIGLEC1_SLC1A2_FAM20A_OLAH SIGLEC1_ISG15_OLAH_MMP8 ISG15_HERC6_IL1R2_FAM20A SIGLEC1_ISG15_OLAH_RETN SIGLEC1_FAM20A_OLAH_MMP8 ISG15_HERC6_OLAH_RETN HERC6_IL1R2_FAM20A_OLAH HERC6_SLC1A2_IL1R2_RETN SIGLEC1_SLC1A2_OLAH_MMP8 HERC6_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_SLC1A2_OLAH HERC6_OLAH_RETN_MMP8 SIGLEC1_HERC6_FAM20A_OLAH HERC6_SLC1A2_IL1R2_MMP8 SIGLEC1_SLC1A2_IL1R2_OLAH SIGLEC1_HERC6_SLC1A2_RETN SIGLEC1_ISG15_FAM20A_OLAH ISG15_SLC1A2_OLAH_MMP8 HERC6_IL1R2_FAM20A_MMP8 ISG15_SLC1A2_OLAH_RETN SIGLEC1_HERC6_SLC1A2_OLAH SIGLEC1_ISG15_HERC6_RETN SIGLEC1_HERC6_IL1R2_MMP8 ISG15_SLC1A2_IL1R2_RETN HERC6_IL1R2_FAM20A_RETN ISG15_HERC6_OLAH_MMP8 SIGLEC1_FAM20A_RETN_MMP8 HERC6_FAM20A_RETN_MMP8 SIGLEC1_HERC6_FAM20A_RETN SIGLEC1_ISG15_SLC1A2_RETN SIGLEC1_SLC1A2_OLAH_RETN SIGLEC1_HERC6_RETN_MMP8 SIGLEC1_ISG15_HERC6_IL1R2 ISG15_SLC1A2_IL1R2_MMP8 SIGLEC1_FAM20A_OLAH_RETN ISG15_IL1R2_OLAH_MMP8 SIGLEC1_HERC6_IL1R2_OLAH SIGLEC1_HERC6_SLC1A2_MMP8 SIGLEC1_IL1R2_OLAH_MMP8 HERC6_SLC1A2_FAM20A_MMP8 HERC6_SLC1A2_IL1R2_FAM20A ISG15_IL1R2_OLAH_RETN SIGLEC1_SLC1A2_IL1R2_MMP8 SIGLEC1_SLC1A2_RETN_MMP8 SIGLEC1_ISG15_SLC1A2_IL1R2 ISG15_HERC6_SLC1A2_FAM20A SIGLEC1_HERC6_SLC1A2_IL1R2 ISG15_HERC6_FAM20A_MMP8 SIGLEC1_SLC1A2_IL1R2_RETN ISG15_HERC6_SLC1A2_RETN HERC6_SLC1A2_FAM20A_OLAH ISG15_IL1R2_RETN_MMP8 SIGLEC1_ISG15_FAM20A_RETN SIGLEC1_ISG15_SLC1A2_MMP8 SIGLEC1_ISG15_IL1R2_MMP8 SLC1A2_IL1R2_FAM20A_OLAH SIGLEC1_SLC1A2_FAM20A_MMP8 ISG15_FAM20A_OLAH_MMP8 SIGLEC1_ISG15_IL1R2_OLAH SLC1A2_FAM20A_OLAH_MMP8 SIGLEC1_ISG15_SLC1A2_FAM20A ISG15_FAM20A_OLAH_RETN SIGLEC1_HERC6_IL1R2_RETN ISG15_HERC6_RETN_MMP8 SIGLEC1_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_RETN_MMP8 SIGLEC1_HERC6_SLC1A2_FAM20A SLC1A2_FAM20A_OLAH_RETN HERC6_FAM20A_OLAH_RETN SIGLEC1_ISG15_HERC6_SLC1A2 SIGLEC1_IL1R2_RETN_MMP8 ISG15_OLAH_RETN_MMP8 HERC6_FAM20A_OLAH_MMP8 HERC6_SLC1A2_RETN_MMP8 ISG15_HERC6_FAM20A_OLAH ISG15_HERC6_SLC1A2_MMP8 ISG15_SLC1A2_IL1R2_FAM20A SLC1A2_IL1R2_OLAH_RETN SIGLEC1_ISG15_HERC6_FAM20A SIGLEC1_ISG15_HERC6_MMP8 ISG15_IL1R2_FAM20A_OLAH SLC1A2_IL1R2_OLAH_MMP8 SIGLEC1_ISG15_FAM20A_MMP8 ISG15_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_IL1R2_RETN SLC1A2_OLAH_RETN_MMP8 SIGLEC1_IL1R2_OLAH_RETN IL1R2_FAM20A_OLAH_MMP8 SIGLEC1_HERC6_FAM20A_MMP8 ISG15_SLC1A2_FAM20A_MMP8 ISG15_HERC6_FAM20A_RETN IL1R2_FAM20A_OLAH_RETN ISG15_IL1R2_FAM20A_MMP8 ISG15_FAM20A_RETN_MMP8 ISG15_HERC6_IL1R2_RETN SLC1A2_IL1R2_FAM20A_MMP8 ISG15_SLC1A2_FAM20A_OLAH SLC1A2_IL1R2_FAM20A_RETN SIGLEC1_HERC6_OLAH_MMP8 ISG15_SLC1A2_RETN_MMP8 ISG15_HERC6_IL1R2_MMP8 IL1R2_OLAH_RETN_MMP8 ISG15_HERC6_IL1R2_OLAH FAM20A_OLAH_RETN_MMP8 SIGLEC1_HERC6_OLAH_RETN IL1R2_FAM20A_RETN_MMP8 ISG15_HERC6_SLC1A2_OLAH SLC1A2_IL1R2_RETN_MMP8 ISG15_IL1R2_FAM20A_RETN HERC6_SLC1A2_OLAH_MMP8 SIGLEC1_OLAH_RETN_MMP8 SIGLEC1_ISG15_HERC6_OLAH HERC6_SLC1A2_IL1R2_OLAH

Preferably, according to this variant, the measurement step comprises or consists of measuring the expression of a combination of four target genes chosen from the following combinations: SIGLEC1_IL1R2_FAM20A_MMP8, SIGLEC1_HERC6_IL1R2_FAM20A, SIGLEC1_ISG15_IL1R2_FAM20A, SIGLEC1_IL1R2_FAM20A_OLAH, SIGLEC1_IL1 R2_FAM20A_RETN, SIGLEC1_SLC1A2_IL1R2_FAM20A, SIGLEC1_SLC1A2_FAM20A_OLAH, ISG15_HERC6_IL1R2_FAM20A, SIGLEC1_FAM20A_OLAH_MMP8, and HERC6_IL1R2_FAM20A_OLAH.

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

According to a variant of this particular embodiment, the measurement 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.

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

According to a variant of this particular embodiment, the measurement 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.

According to a variant of this particular embodiment, the measurement 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.

According to a variant of this particular embodiment, the measurement 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, SLC1A2, OLAH, FAM20A, RETN and IL1R2, preferably from OLAH, SLC1A2, FAM20A and IL1R2.

According to a variant of this particular embodiment, the measurement 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, SLC1A2, OLAH, FAM20A, RETN and MMP8, preferably from IL1R2, OLAH, FAM20A and MMP8.

According to another variant of this particular embodiment, the measurement 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.

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

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

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

Favorite Combinations of 5 Genes SIGLEC1_HERC6_IL1R2_FAM20A_MMP8 SIGLEC1_ISG15_SLC1A2_IL1R2_RETN SIGLEC1_IL1R2_FAM20A_OLAH_MMP8 SIGLEC1_ISG15_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_IL1R2_FAM20A_MMP8 SIGLEC1_HERC6_SLC1A2_IL1R2_RETN SIGLEC1_IL1R2_FAM20A_RETN_MMP8 HERC6_SLC1A2_IL1R2_FAM20A_RETN SIGLEC1_SLC1A2_IL1R2_FAM20A_MMP8 SIGLEC1_HERC6_SLC1A2_OLAH_RETN SIGLEC1_ISG15_HERC6_IL1R2_FAM20A SIGLEC1_SLC1A2_IL1R2_RETN_MMP8 SIGLEC1_HERC6_IL1R2_FAM20A_OLAH SIGLEC1_ISG15_IL1R2_RETN_MMP8 SIGLEC1_SLC1A2_FAM20A_OLAH_MMP8 SIGLEC1_HERC6_SLC1A2_FAM20A_MMP8 SIGLEC1_ISG15_IL1R2_FAM20A_OLAH HERC6_SLC1A2_IL1R2_FAM20A_MMP8 SIGLEC1_ISG15_IL1R2_FAM20A_RETN HERC6_FAM20A_OLAH_RETN_MMP8 SIGLEC1_HERC6_IL1R2_FAM20A_RETN SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A HERC6_SLC1A2_FAM20A_OLAH_RETN SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH ISG15_HERC6_FAM20A_OLAH_RETN SIGLEC1_IL1R2_FAM20A_OLAH_RETN SIGLEC1_IL1R2_OLAH_RETN_MMP8 SIGLEC1_SLC1A2_IL1R2_FAM20A_RETN SIGLEC1_ISG15_HERC6_IL1R2_RETN SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A SIGLEC1_HERC6_IL1R2_OLAH_RETN SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH ISG15_HERC6_FAM20A_OLAH_MMP8 SIGLEC1_HERC6_SLC1A2_FAM20A_OLAH SIGLEC1_ISG15_HERC6_FAM20A_MMP8 SIGLEC1_HERC6_FAM20A_OLAH_MMP8 SIGLEC1_ISG15_IL1R2_OLAH_RETN SIGLEC1_FAM20A_OLAH_RETN_MMP8 SIGLEC1_HERC6_OLAH_RETN_MMP8 SIGLEC1_ISG15_FAM20A_OLAH_MMP8 ISG15_IL1R2_FAM20A_OLAH_MMP8 ISG15_HERC6_IL1R2_FAM20A_OLAH ISG15_SLC1A2_IL1R2_FAM20A_RETN SIGLEC1_SLC1A2_FAM20A_OLAH_RETN ISG15_HERC6_IL1R2_RETN_MMP8 ISG15_HERC6_IL1R2_FAM20A_MMP8 ISG15_SLC1A2_IL1R2_FAM20A_MMP8 ISG15_HERC6_IL1R2_FAM20A_RETN SIGLEC1_ISG15_HERC6_OLAH_RETN HERC6_IL1R2_FAM20A_OLAH_MMP8 ISG15_HERC6_SLC1A2_IL1R2_OLAH SIGLEC1_ISG15_HERC6_FAM20A_OLAH ISG15_HERC6_SLC1A2_OLAH_MMP8 SIGLEC1_HERC6_FAM20A_RETN_MMP8 ISG15_HERC6_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_SLC1A2_OLAH_MMP8 SIGLEC1_ISG15_HERC6_OLAH_MMP8 SIGLEC1_SLC1A2_IL1R2_OLAH_MMP8 ISG15_HERC6_SLC1A2_OLAH_RETN SIGLEC1_ISG15_SLC1A2_IL1R2_OLAH SIGLEC1_ISG15_OLAH_RETN_MMP8 SIGLEC1_HERC6_FAM20A_OLAH_RETN ISG15_IL1R2_FAM20A_OLAH_RETN SIGLEC1_HERC6_SLC1A2_OLAH_MMP8 ISG15_SLC1A2_FAM20A_OLAH_MMP8 HERC6_IL1R2_FAM20A_OLAH_RETN HERC6_SLC1A2_IL1R2_OLAH_RETN SIGLEC1_ISG15_HERC6_FAM20A_RETN ISG15_HERC6_IL1R2_OLAH_MMP8 SIGLEC1_ISG15_FAM20A_RETN_MMP8 ISG15_HERC6_IL1R2_OLAH_RETN SIGLEC1_SLC1A2_IL1R2_OLAH_RETN ISG15_IL1R2_FAM20A_RETN_MMP8 SIGLEC1_HERC6_IL1R2_OLAH_MMP8 HERC6_IL1R2_OLAH_RETN_MMP8 SIGLEC1_HERC6_SLC1A2_IL1R2_OLAH HERC6_SLC1A2_OLAH_RETN_MMP8 SIGLEC1_ISG15_HERC6_SLC1A2_OLAH ISG15_HERC6_SLC1A2_IL1R2_RETN SIGLEC1_ISG15_HERC6_IL1R2_MMP8 HERC6_SLC1A2_IL1R2_OLAH_MMP8 ISG15_HERC6_SLC1A2_IL1R2_FAM20A ISG15_HERC6_FAM20A_RETN_MMP8 SIGLEC1_SLC1A2_FAM20A_RETN_MMP8 ISG15_HERC6_SLC1A2_IL1R2_MMP8 HERC6_SLC1A2_IL1R2_FAM20A_OLAH ISG15_SLC1A2_FAM20A_OLAH_RETN SIGLEC1_ISG15_FAM20A_OLAH_RETN ISG15_HERC6_OLAH_RETN_MMP8 SIGLEC1_ISG15_SLC1A2_OLAH_RETN ISG15_SLC1A2_IL1R2_OLAH_RETN SIGLEC1_HERC6_IL1R2_RETN_MMP8 ISG15_SLC1A2_IL1R2_OLAH_MMP8 HERC6_IL1R2_FAM20A_RETN_MMP8 SIGLEC1_ISG15_HERC6_SLC1A2_RETN SIGLEC1_HERC6_SLC1A2_IL1R2_MMP8 HERC6_SLC1A2_IL1R2_RETN_MMP8 SIGLEC1_SLC1A2_OLAH_RETN_MMP8 HERC6_SLC1A2_FAM20A_RETN_MMP8 ISG15_SLC1A2_IL1R2_FAM20A_OLAH SIGLEC1_HERC6_SLC1A2_RETN_MMP8 SIGLEC1_HERC6_SLC1A2_FAM20A_RETN SIGLEC1_ISG15_HERC6_RETN_MMP8 SIGLEC1_ISG15_HERC6_IL1R2_OLAH ISG15_HERC6_SLC1A2_FAM20A_MMP8 SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2 ISG15_SLC1A2_OLAH_RETN_MMP8 ISG15_HERC6_SLC1A2_FAM20A_OLAH SIGLEC1_ISG15_SLC1A2_RETN_MMP8 SIGLEC1_ISG15_SLC1A2_IL1R2_MMP8 SIGLEC1_ISG15_HERC6_SLC1A2_MMP8 SIGLEC1_ISG15_IL1R2_OLAH_MMP8 ISG15_SLC1A2_IL1R2_RETN_MMP8 SIGLEC1_ISG15_SLC1A2_FAM20A_MMP8 ISG15_IL1R2_OLAH_RETN_MMP8 HERC6_SLC1A2_FAM20A_OLAH_MMP8 ISG15_FAM20A_OLAH_RETN_MMP8 SLC1A2_FAM20A_OLAH_RETN_MMP8 SLC1A2_IL1R2_FAM20A_OLAH_MMP8 SLC1A2_IL1R2_OLAH_RETN_MMP8 ISG15_HERC6_SLC1A2_RETN_MMP8 ISG15_SLC1A2_FAM20A_RETN_MMP8 SLC1A2_IL1R2_FAM20A_OLAH_RETN IL1R2_FAM20A_OLAH_RETN_MMP8 SLC1A2_IL1R2_FAM20A_RETN_MMP8

Preferably, according to this variant, the measurement step comprises or consists of measuring the expression of a combination of five target genes chosen from the following combinations:
- SIGLEC1_HERC6_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_OLAH_MMP8
- SIGLEC1_ISG15_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_RETN_MMP8
- SIGLEC1_SLC1A2_IL1R2_FAM20A_MMP8
- SIGLEC1_ISG15_HERC6_IL1R2_FAM20A
- SIGLEC1_HERC6_IL1R2_FAM20A_OLAH
- SIGLEC1_SLC1A2_FAM20A_OLAH_MMP8, and
- SIGLEC1_ISG15_IL1R2_FAM20A_OLAH.

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

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

According to a variant of this particular embodiment, the measurement 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.

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

According to another variant of this particular embodiment, the measurement 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, SLC1A2, OLAH , FAM20A, RETN and MMP8.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of a combination of six target genes chosen from the following combinations:
SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_MMP8 ;
SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_MMP8 ;
SIGLEC1_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_OLAH ;
SIGLEC1_HERC6_SLC1A2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_OLAH ;
SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_RETN ;
SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_RETN ;
SIGLEC1_HERC6_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_OLAH ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_RETN ;
SIGLEC1_ISG15_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH_RETN ;
ISG15_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_FAM20A_RETN_MMP8 ;
ISG15_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_HERC6_SLC1A2_FAM20A_OLAH_RETN ;
ISG15_HERC6_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_SLC1A2_IL1R2_OLAH_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_OLAH_MMP8 ;
HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_HERC6_SLC1A2_FAM20A_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_OLAH ;
SIGLEC1_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_OLAH_RETN ;
HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_RETN ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_RETN ;
SIGLEC1_ISG15_HERC6_IL1R2_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_OLAH_RETN_MMP8 ;
SIGLEC1_HERC6_IL1R2_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_OLAH_MMP8 ;
SIGLEC1_HERC6_SLC1A2_OLAH_RETN_MMP8 ;
HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_OLAH_RETN ;
ISG15_HERC6_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_OLAH_RETN ;
SIGLEC1_HERC6_SLC1A2_IL1R2_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN ;
HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_MMP8 ;
ISG15_HERC6_SLC1A2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_RETN_MMP8 ;
HERC6_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_RETN ;
SIGLEC1_ISG15_IL1R2_OLAH_RETN_MMP8 ;
ISG15_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_OLAH_RETN ;
ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_OLAH_RETN_MMP8 ;
ISG15_HERC6_IL1R2_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_OLAH_RETN ;
ISG15_HERC6_SLC1A2_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_OLAH_MMP8 ;
HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;
ISG15_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_FAM20A_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_RETN_MMP8 ;
ISG15_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_RETN_MMP8 ;
ISG15_SLC1A2_IL1R2_OLAH_RETN_MMP8 ; And
SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8.

Preferably, according to this variant, the measurement step comprises or consists of measuring the expression of a combination of six target genes chosen from the following combinations:
SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_MMP8 ;
SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_IL1R2_FAM20A_RETN_MMP8 ; And
SIGLEC1_IL1R2_FAM20A_OLAH_RETN_MMP8

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of at least seven target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

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

According to a variant of this particular embodiment, the measurement step 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 SIGLEC1.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

According to another variant of this particular embodiment, the measurement 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.

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

SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
IGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH ;
SIGLEC1_ISG15_HERC6_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_RETN ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN ;
ISG15_HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_OLAH_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_OLAH_RETN_MMP8 ;
ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_OLAH_RETN ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_RETN_MMP8 ;
ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
and ISG15_HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8.

Preferably, according to this variant, the measurement step comprises or consists of measuring the expression of seven target genes chosen from the following combinations:
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
IGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_MMP8 ; And
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_RETN_MMP8.

According to another particular embodiment, the measurement step comprises or consists of measuring the expression of at least eight target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

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

According to another variant of this particular embodiment, the measurement 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.

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

According to another variant of this particular embodiment, the measurement step comprises or consists of measuring the expression of a combination of eight target genes chosen from the following combinations:
SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
SIGLEC1_ISG15_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_RETN_MMP8 ;
SIGLEC1_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_FAM20A_OLAH_RETN_MMP8 ;
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN ;
ISG15_HERC6_SLC1A2_IL1R2_FAM20A_OLAH_RETN_MMP8, and
SIGLEC1_ISG15_HERC6_SLC1A2_IL1R2_OLAH_RETN_MMP8.

According to another particular embodiment, the method includes a step of measuring the variation in the expression of the nine target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

By “biological sample”, we refer in this description to any sample coming from a subject and which may be of different natures, such as blood or its derivatives, sputum, urine, stools, skin, liquid 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.

The expression "biological reference sample", or "control sample", refers to the biological sample from which the expression levels of the target genes, and possibly those of additional genes, in the biological sample to be tested are compared. . The biological reference 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 the determination of the expression level 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.

According to a particular embodiment, the biological reference sample is calibrated to contain the quantity of transcripts of at least two target genes, and possibly 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 with 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.

In particular, the biological sample may be a biological fluid, such as a blood sample or a sample derived from blood, which may in particular be chosen from whole blood (as collected venously, that is to say containing white and red cells, platelets and plasma), plasma, serum, as well as all types of cells extracted from blood, such as 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 even neutrophils.

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.

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 even at least 95%. 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:

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%.

Specificity corresponds to the probability of incorrectly identifying the viral or bacterial nature of the infection. In other words, to identify the presence of a viral infection when it is a bacterial infection, or vice versa. Specificity can be defined by the following formula:

The sensitivity and specificity of a diagnostic test, such as the method according to the present invention, can also be summarized via a ROC (Receiver Operating Characteristics) curve, in particular the area under the ROC curve, which is well known to those skilled in the art.

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

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: RSAD2, IFI27, OAS1, IFIT1, IFI44L, PI3, EBI3, ADGRE1 and S100P.

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

[table 5]: Additional biomarker Chromosomal location (GRCh38/hg38) English name RSAD2 Chr2: 6865557-6898239 Radical S-Adenosyl Methionine Domain Containing 2 IFI27 Chr14:94104836-94116698 Interferon Alpha Inducible Protein 27 OAS1 Chr12: 112905856-112933219 2'-5'-Oligoadenylate Synthetase 1 IFIT1 Chr10: 89392546-89406487 Interferon Induced Protein With Tetratricopeptide Repeats 1 IFI44L Chr1: 78619902-78646145 Interferon Induced Protein 44 Like PI3 Chr20:45174902-45176544 Peptidase Inhibitor 3 EBI3 Chr19:4229523-4237528 Epstein-Barr Virus Induced 3 ADGRE1 Chr19:6887566-6940459 Adhesion G Protein-Coupled Receptor E1 S100P Chr4: 6693878-6697170 S100 Calcium Binding Protein P

In the same way as above, for a given additional gene, the reference value corresponds to a level of expression of transcripts of said gene obtained from a biological reference 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 a infection.

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 can be concluded that there is an infection of a viral nature when the comparison of the level of expression of additional genes at the level of mRNA transcripts compared to the respective reference values highlights at least one variation in expression chosen. among :
- overexpression of RSAD2,
- overexpression of IFI27,
- overexpression of OAS1,
- overexpression of IFIT1,
- overexpression of IFI44L,
- a subexpression of PI3,
- a subexpression of EBI3,
- a subexpression of ADGRE1, and
- a subexpression of S100P.

According to a second variant, the reference value of each additional gene is determined from a biological reference sample from subjects suffering from a viral infection. Thus, it can be concluded that an infection of a bacterial nature is present when the comparison of the level of expression of additional genes at the level of mRNA transcripts compared to the respective reference values highlights at least one variation in expression chosen. among :
- a subexpression of RSAD2,
- a subexpression of IFI27,
- a subexpression of OAS1,
- a subexpression of IFIT1,
- a subexpression of IFI44L,
- overexpression of PI3,
- overexpression of EBI3,
- overexpression of ADGRE1, and
- overexpression of S100P.

According to a particular embodiment, the method according to the invention comprises measuring the variation in the expression of all of 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.

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 reference values determined.

Thus, according to a particular embodiment, the method comprises the steps:
- obtaining a biological blood sample, preferably whole blood, from a subject with an infection,
- bringing said biological sample into contact with reagents specific for the expression products of the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and possibly one or more additional genes chosen from RSAD2, IFI27, OAS1, IFIT1, IFI44L, PI3, EBI3, ADGRE1 and S100P
- measurement of the expression of said target genes, and possibly additional gene(s).

Another object of the invention relates to a kit for measuring in vitro or ex vivo the expression of at least two target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, 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 target genes.

In particular, the kit allows the implementation of the method according to the invention. Thus, 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.

The specific reagents allowing gene expression to be measured are known to those skilled in the art and according to a particular embodiment, these are amplification primers and/or hybridization probes.

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

By kit, we mean 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 in the context of the invention. The necessary reagents may or may not be grouped together in the same kit or device.

The term “amplification primer” or “primer” means a nucleotide fragment which may consist of 5 to 100 nucleotides, preferably 15 to 30 nucleotides, and having hybridization specificity 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, “pairs of primers” 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 pairs of primers are preferably used, each preferably having an ability to hybridize specifically with a different biomarker.

The person skilled in the art is entirely able, from the sequence of a gene, and in particular from the sequence of the corresponding transcripts, for example those listed in Table 2, to determine the nucleotide sequences of the primers in order to allow amplification. transcripts.

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 previously.

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 hybridization specificity. under specific conditions to form a hybridization complex with a target nucleotide sequence. The probe also includes a reporter (such as a fluorophore, an enzyme or any other detection system), which will allow 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 different biomarkers (e.g. genes or mRNAs of said genes), several different probes are preferably used, each preferably having an ability to hybridize specifically with a different biomarker.

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.

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 stringency, that is to say the rigor of the operating conditions. The hybridization is all the more specific as it is carried out at higher stringency.

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. The stringency can also be a function of the 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 must be carried out will depend mainly on the hybridization probes used. All these data are well known and the appropriate conditions can be determined by those skilled in the art.

In general, depending on the length of the hybridization probes used, the temperature for the hybridization reaction is between approximately 20 and 70°C, in particular between 35 and 65°C in a saline solution at a concentration of approximately 0 .5 to 1 M. A step of detecting the hybridization reaction is then carried out.

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 possibly 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 with a bacterial infection and/or a control sample calibrated to contain the quantity of transcripts of at least two target genes, and possibly one or more additional genes, corresponding to the quantity or at the concentration representative of the expression level measured in a pool of samples from subjects with a viral infection.

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 having a bacterial infection or from subjects having a viral infection.

According to one embodiment, the reagents specific for the expression of 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 of each selected housekeeping gene, or even one or more oligonucleotide(s) suitable for the detection of 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 more details.

The kit, in all its embodiments, may also comprise reagents specific for the expression products of one or more additional genes chosen from RSAD2, IFI27, OAS1, IFIT1, IFI44L, PI3, EBI3, ADGRE1 and S100P and their combinations.

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

The kit, in all its embodiments, may also include reagents specific for the expression products of one or more housekeeping genes. Here again, the kit according to the invention may comprise reagents specific to the expression products of each selected housekeeping gene.

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 pocket. Such a consumable is particularly intended for use with the BioFire® FilmArray® V2.0 and Torch systems.

Another object concerns the use of a kit as defined above to determine the viral or bacterial nature of an infection in a subject.

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 gene chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and possibly one or more additional genes as defined above, in a biological blood sample from a subject presenting an infection.

The description also concerns the 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.

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. For example, the antiviral agent can be chosen from the following agents: amantadine, rimantadine, ritonavir, cobicistat, interferon alfa-2b/ribavirin, ombitasvir/paritaprevir/ritonavir, peginterferon alfa-2a, peginterferon alfa-2b, maraviroc , raltegravir, dolutegravir, elvitegravir, sofosbuvir, enfuvirtide, foscarnet, fomivirsen, zanamivir, oseltamivir, peramivir, nevirapine, etravirine, efavirenz, rilpivirine, delavirdine, nevirapine, daclatasvir, entacavir, lamivudine, adefovir, didanosine, tenofovir, a bacavir, 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 and cidofovir .

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 can 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, cefepi me, ceftobiprole, fluorquinolones, piperacillin/tazobactam, ticarcillin/clavulanic acid, linezolid, streptogramins, daptomycin, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, spectinomycin, geldanamycin, herbimycin and rifaximin.

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

Examples 1. Material and method

1.1 Clinical characteristics of patients & samples

Clinical whole blood samples were collected in PAXgene® tubes upon patient admission to the emergency department (D0) following the manufacturer's recommendations. In total, 191 samples were collected with the following distribution: 68 samples from a characterized bacterial infection and 123 samples from a characterized viral infection.

The origin and distribution of the samples are summarized below:

Patients: Female – 82 (42.9%); Male 109(57.1%)

Average age: 3.4 years

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

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

Probable bacterial infection, n(%): 16 (8.4)

Viral infection, n(%): 123 (64.4)

1.2. Identification and validation of biomarkers

A first selection of transcriptomic biomarkers characteristic of viral and bacterial infections was carried out using the Applicant's internal database. Several hundred biomarkers have been identified.

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

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. Several dozen biomarkers were thus selected.

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 validation. independent of performance.

To evaluate the individual performance of the biomarkers, the area under the ROC curve was calculated with a 95% confidence index (95% CI). Regarding the performance of the combinations, analyzes were carried out using complex classifiers based on machine learning using R version 3.6.1.

Two methods were particularly 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 which contribute the most in the machine learning model to classify patients and allow the identification of the nature of the infection (viral or bacterial).

The second method is the "FeatureImp" function of the IML package which returns the factor by which the model's prediction error increases when a feature is mixed.

Ultimately, nine biomarkers were retained following the selection, namely the following biomarkers: SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8.

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

2. Results 2.1 BoxPlot

BoxPlot analysis reveals the overexpression/underexpression of different target genes depending on the nature of the infection. Thus, when we compare the expressions of target genes between viral and bacterial infections, we see that the SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP genes are overexpressed during bacterial infection while the SIGLEC1, ISG15 genes and HERC6 are overexpressed during viral infection compared.

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 performances were evaluated several times and the AUCs of the model therefore correspond to the average of the different AUCs obtained.

Performance obtained for identifying the viral or bacterial nature of the infection based on 2-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1_IL1R2 0.890 0.882 0.898 0.897 0.835 0.959 0.960 0.920 1 SIGLEC1_FAM20A 0.888 0.878 0.897 0.890 0.817 0.963 0.955 0.893 1 HERC6_IL1R2 0.885 0.877 0.893 0.895 0.836 0.954 0.927 0.865 0.990 SIGLEC1_OLAH 0.882 0.873 0.890 0.890 0.821 0.959 0.949 0.900 0.998 HERC6_OLAH 0.876 0.867 0.885 0.886 0.819 0.953 0.941 0.889 0.993 ISG15_IL1R2 0.874 0.866 0.882 0.885 0.824 0.945 0.933 0.865 1 SIGLEC1_RETN 0.869 0.859 0.879 0.875 0.797 0.953 0.948 0.898 0.997 HERC6_FAM20A 0.866 0.856 0.876 0.874 0.802 0.945 0.925 0.838 1 SLC1A2_OLAH 0.865 0.855 0.874 0.880 0.817 0.942 0.845 0.737 0.952 HERC6_RETN 0.864 0.853 0.874 0.872 0.795 0.950 0.928 0.867 0.990 SIGLEC1_SLC1A2 0.864 0.855 0.872 0.877 0.811 0.944 0.957 0.914 0.999 ISG15_OLAH 0.863 0.854 0.872 0.873 0.805 0.941 0.940 0.886 0.994 SIGLEC1_MMP8 0.858 0.848 0.868 0.863 0.786 0.940 0.926 0.866 0.987 HERC6_MMP8 0.851 0.841 0.862 0.859 0.784 0.935 0.877 0.791 0.964 IL1R2_OLAH 0.851 0.842 0.860 0.862 0.796 0.928 0.843 0.733 0.954 IL1R2_FAM20A 0.847 0.839 0.856 0.863 0.797 0.929 0.849 0.736 0.962 SIGLEC1_HERC6 0.847 0.837 0.857 0.854 0.778 0.930 0.946 0.896 0.995 HERC6_SLC1A2 0.842 0.833 0.851 0.857 0.787 0.926 0.902 0.820 0.984 SIGLEC1_ISG15 0.842 0.832 0.852 0.849 0.772 0.927 0.945 0.895 0.994 FAM20A_OLAH 0.839 0.829 0.849 0.852 0.782 0.922 0.871 0.776 0.965 ISG15_FAM20A 0.838 0.828 0.848 0.846 0.769 0.923 0.924 0.844 1 SLC1A2_IL1R2 0.838 0.829 0.846 0.852 0.785 0.918 0.826 0.709 0.943 ISG15_RETN 0.836 0.827 0.846 0.851 0.777 0.926 0.949 0.896 1 OLAH_MMP8 0.836 0.826 0.845 0.847 0.778 0.916 0.861 0.761 0.960 OLAH_RETN 0.834 0.824 0.844 0.850 0.780 0.921 0.848 0.738 0.958 ISG15_HERC6 0.829 0.819 0.840 0.839 0.763 0.914 0.921 0.856 0.986 IL1R2_MMP8 0.828 0.820 0.836 0.849 0.781 0.916 0.812 0.696 0.928 IL1R2_RETN 0.828 0.819 0.837 0.850 0.782 0.918 0.820 0.705 0.935 ISG15_MMP8 0.819 0.810 0.829 0.832 0.754 0.910 0.898 0.823 0.972 ISG15_SLC1A2 0.803 0.793 0.813 0.820 0.744 0.895 0.911 0.839 0.983

Performance obtained for identifying the viral or bacterial nature of the infection based on three-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1_IL1R2_FAM20A 0.896 0.888 0.905 0.909 0.846 0.973 0.963 0.912 1 HERC6_IL1R2_FAM20A 0.892 0.883 0.900 0.907 0.847 0.966 0.922 0.833 1 SIGLEC1_SLC1A2_OLAH 0.892 0.883 0.900 0.912 0.857 0.968 0.951 0.904 0.998 SIGLEC1_HERC6_IL1R2 0.889 0.881 0.897 0.902 0.841 0.962 0.953 0.909 0.998 SIGLEC1_FAM20A_OLAH 0.889 0.879 0.898 0.897 0.825 0.969 0.962 0.918 1 SIGLEC1_IL1R2_MMP8 0.887 0.879 0.895 0.901 0.842 0.960 0.962 0.923 1 SIGLEC1_ISG15_IL1R2 0.886 0.878 0.894 0.899 0.837 0.961 0.962 0.923 1 SIGLEC1_SLC1A2_IL1R2 0.886 0.878 0.894 0.908 0.853 0.964 0.964 0.927 1 SIGLEC1_IL1R2_OLAH 0.885 0.877 0.894 0.901 0.840 0.963 0.960 0.918 1 SIGLEC1_SLC1A2_FAM20A 0.885 0.876 0.894 0.902 0.839 0.966 0.949 0.877 1 HERC6_FAM20A_OLAH 0.884 0.875 0.894 0.898 0.833 0.963 0.942 0.875 1 SIGLEC1_FAM20A_RETN 0.884 0.875 0.894 0.893 0.821 0.966 0.954 0.895 1 SIGLEC1_HERC6_FAM20A 0.884 0.874 0.894 0.893 0.821 0.965 0.952 0.879 1 SIGLEC1_FAM20A_MMP8 0.883 0.873 0.893 0.890 0.817 0.964 0.959 0.897 1 SIGLEC1_IL1R2_RETN 0.883 0.874 0.891 0.896 0.832 0.961 0.960 0.918 1 ISG15_IL1R2_FAM20A 0.882 0.874 0.891 0.900 0.838 0.961 0.926 0.844 1 SIGLEC1_ISG15_FAM20A 0.882 0.873 0.892 0.890 0.816 0.963 0.955 0.893 1 ISG15_HERC6_IL1R2 0.882 0.874 0.890 0.895 0.836 0.954 0.941 0.888 0.995 HERC6_IL1R2_OLAH 0.879 0.870 0.888 0.898 0.839 0.957 0.935 0.878 0.991 SIGLEC1_HERC6_OLAH 0.879 0.870 0.888 0.893 0.825 0.961 0.957 0.914 0.999 HERC6_SLC1A2_OLAH 0.879 0.870 0.888 0.902 0.844 0.960 0.937 0.880 0.993 HERC6_IL1R2_RETN 0.878 0.869 0.887 0.893 0.829 0.958 0.929 0.869 0.990 HERC6_IL1R2_MMP8 0.877 0.869 0.886 0.896 0.837 0.955 0.926 0.865 0.988 SIGLEC1_OLAH_MMP8 0.877 0.868 0.887 0.890 0.822 0.958 0.954 0.910 0.999 SIGLEC1_ISG15_OLAH 0.876 0.867 0.885 0.890 0.821 0.959 0.949 0.900 0.998 SIGLEC1_OLAH_RETN 0.876 0.866 0.885 0.890 0.819 0.961 0.945 0.890 0.999 HERC6_SLC1A2_IL1R2 0.876 0.867 0.885 0.901 0.847 0.956 0.914 0.835 0.993 ISG15_SLC1A2_OLAH 0.875 0.866 0.883 0.895 0.835 0.954 0.922 0.854 0.989 HERC6_FAM20A_RETN 0.875 0.864 0.885 0.887 0.816 0.958 0.939 0.861 1 HERC6_OLAH_RETN 0.874 0.864 0.884 0.889 0.818 0.959 0.942 0.891 0.993 ISG15_SLC1A2_IL1R2 0.872 0.864 0.880 0.894 0.836 0.952 0.917 0.838 0.997 HERC6_OLAH_MMP8 0.872 0.862 0.881 0.887 0.820 0.955 0.941 0.889 0.994 SIGLEC1_HERC6_RETN 0.871 0.861 0.881 0.878 0.799 0.958 0.959 0.916 1 ISG15_IL1R2_OLAH 0.871 0.862 0.879 0.889 0.827 0.950 0.938 0.876 1,000 ISG15_HERC6_OLAH 0.870 0.861 0.880 0.885 0.818 0.952 0.950 0.904 0.996 SIGLEC1_SLC1A2_RETN 0.870 0.861 0.879 0.893 0.829 0.957 0.950 0.902 0.998 ISG15_IL1R2_RETN 0.867 0.859 0.876 0.889 0.827 0.952 0.935 0.869 1 ISG15_FAM20A_OLAH 0.867 0.857 0.877 0.887 0.820 0.954 0.945 0.892 0.997 ISG15_IL1R2_MMP8 0.866 0.858 0.874 0.884 0.824 0.944 0.933 0.865 1,000 SIGLEC1_SLC1A2_MMP8 0.866 0.857 0.874 0.884 0.819 0.949 0.937 0.882 0.992 ISG15_HERC6_RETN 0.865 0.855 0.876 0.878 0.801 0.955 0.954 0.908 1 SIGLEC1_ISG15_RETN 0.864 0.854 0.874 0.875 0.798 0.952 0.953 0.907 0.999 HERC6_SLC1A2_FAM20A 0.864 0.854 0.874 0.886 0.824 0.949 0.928 0.843 1 ISG15_HERC6_FAM20A 0.864 0.854 0.874 0.875 0.803 0.947 0.930 0.845 1 HERC6_FAM20A_MMP8 0.863 0.853 0.874 0.878 0.808 0.949 0.927 0.845 1 SLC1A2_FAM20A_OLAH 0.863 0.853 0.872 0.884 0.822 0.945 0.859 0.754 0.963 SIGLEC1_RETN_MMP8 0.861 0.851 0.872 0.873 0.796 0.951 0.953 0.906 1 HERC6_SLC1A2_RETN 0.861 0.851 0.871 0.885 0.818 0.953 0.933 0.866 0.999 SIGLEC1_HERC6_SLC1A2 0.860 0.852 0.869 0.877 0.810 0.944 0.954 0.908 1 SLC1A2_IL1R2_OLAH 0.859 0.850 0.868 0.877 0.815 0.939 0.842 0.733 0.952 SIGLEC1_HERC6_MMP8 0.859 0.849 0.869 0.871 0.795 0.947 0.914 0.848 0.981 ISG15_OLAH_RETN 0.859 0.849 0.868 0.879 0.810 0.948 0.948 0.894 1 SIGLEC1_ISG15_SLC1A2 0.858 0.850 0.866 0.878 0.811 0.944 0.954 0.910 0.998 ISG15_OLAH_MMP8 0.858 0.849 0.867 0.875 0.807 0.942 0.943 0.892 0.995 SLC1A2_OLAH_MMP8 0.858 0.849 0.867 0.879 0.817 0.941 0.855 0.754 0.957 SLC1A2_OLAH_RETN 0.858 0.848 0.867 0.878 0.815 0.941 0.842 0.733 0.952 HERC6_RETN_MMP8 0.857 0.846 0.867 0.870 0.792 0.948 0.916 0.850 0.983 HERC6_SLC1A2_MMP8 0.855 0.845 0.864 0.875 0.807 0.943 0.892 0.809 0.976 SIGLEC1_ISG15_MMP8 0.851 0.841 0.861 0.865 0.788 0.941 0.926 0.866 0.986 IL1R2_FAM20A_OLAH 0.850 0.840 0.859 0.870 0.806 0.935 0.859 0.755 0.962 ISG15_HERC6_MMP8 0.849 0.839 0.859 0.865 0.791 0.939 0.899 0.824 0.974 ISG15_SLC1A2_FAM20A 0.847 0.837 0.857 0.864 0.792 0.935 0.912 0.822 1 ISG15_FAM20A_RETN 0.846 0.836 0.856 0.869 0.799 0.938 0.938 0.867 1 IL1R2_OLAH_MMP8 0.844 0.835 0.853 0.865 0.801 0.928 0.850 0.746 0.954 SLC1A2_IL1R2_FAM20A 0.844 0.835 0.853 0.867 0.803 0.930 0.846 0.728 0.963 IL1R2_OLAH_RETN 0.841 0.831 0.851 0.864 0.798 0.930 0.845 0.734 0.955 SIGLEC1_ISG15_HERC6 0.840 0.830 0.850 0.854 0.778 0.931 0.942 0.891 0.993 FAM20A_OLAH_MMP8 0.839 0.829 0.849 0.861 0.795 0.927 0.876 0.785 0.967 ISG15_SLC1A2_RETN 0.838 0.829 0.848 0.865 0.797 0.933 0.927 0.863 0.992 IL1R2_FAM20A_MMP8 0.837 0.829 0.846 0.863 0.798 0.928 0.854 0.745 0.963 ISG15_HERC6_SLC1A2 0.836 0.827 0.845 0.859 0.790 0.927 0.922 0.848 0.995 ISG15_SLC1A2_MMP8 0.836 0.827 0.845 0.861 0.792 0.931 0.896 0.817 0.974 ISG15_FAM20A_MMP8 0.835 0.825 0.845 0.855 0.780 0.930 0.929 0.854 1 IL1R2_FAM20A_RETN 0.834 0.825 0.844 0.862 0.796 0.928 0.847 0.733 0.961 SLC1A2_IL1R2_RETN 0.831 0.822 0.840 0.854 0.788 0.921 0.822 0.702 0.941 FAM20A_OLAH_RETN 0.831 0.821 0.841 0.852 0.782 0.922 0.872 0.777 0.966 OLAH_RETN_MMP8 0.830 0.820 0.840 0.855 0.787 0.924 0.866 0.767 0.966 SLC1A2_IL1R2_MMP8 0.829 0.820 0.837 0.851 0.784 0.918 0.825 0.707 0.943 ISG15_RETN_MMP8 0.828 0.818 0.838 0.849 0.774 0.925 0.941 0.884 0.998 IL1R2_RETN_MMP8 0.815 0.806 0.824 0.847 0.778 0.916 0.817 0.704 0.931

Performance obtained for identifying the viral or bacterial nature of the infection based on 4-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1, IL1R2, FAM20A, MMP8 0.902 0.893 0.910 0.917 0.858 0.976 0.961 0.900 1 SIGLEC1, HERC6, IL1R2, FAM20A 0.895 0.886 0.903 0.912 0.849 0.974 0.958 0.897 1 SIGLEC1, ISG15, IL1R2, FAM20A 0.892 0.883 0.900 0.908 0.845 0.972 0.963 0.912 1 SIGLEC1, IL1R2, FAM20A, OLAH 0.892 0.883 0.900 0.910 0.847 0.973 0.963 0.912 1 SIGLEC1, IL1R2, FAM20A, RETN 0.891 0.882 0.900 0.907 0.844 0.971 0.962 0.907 1 SIGLEC1, SLC1A2, IL1R2, FAM20A 0.889 0.881 0.898 0.916 0.862 0.970 0.954 0.890 1 SIGLEC1, SLC1A2, FAM20A, OLAH 0.889 0.880 0.898 0.913 0.855 0.971 0.950 0.890 1 ISG15, HERC6, IL1R2, FAM20A 0.889 0.880 0.898 0.907 0.847 0.966 0.932 0.849 1 SIGLEC1, FAM20A, OLAH, MMP8 0.887 0.877 0.897 0.901 0.832 0.970 0.965 0.920 1 HERC6, IL1R2, FAM20A, OLAH 0.886 0.877 0.895 0.907 0.847 0.966 0.930 0.853 1 SIGLEC1, SLC1A2, OLAH, MMP8 0.886 0.877 0.895 0.912 0.856 0.967 0.957 0.914 0.999 SIGLEC1, ISG15, SLC1A2, OLAH 0.886 0.877 0.894 0.912 0.856 0.967 0.948 0.899 0.997 SIGLEC1, HERC6, FAM20A, OLAH 0.885 0.875 0.895 0.902 0.834 0.970 0.960 0.907 1 SIGLEC1, SLC1A2, IL1R2, OLAH 0.885 0.876 0.893 0.913 0.858 0.968 0.963 0.925 1 SIGLEC1, ISG15, FAM20A, OLAH 0.884 0.875 0.894 0.897 0.825 0.968 0.962 0.918 1 HERC6, IL1R2, FAM20A, MMP8 0.884 0.876 0.893 0.909 0.852 0.966 0.920 0.828 1 SIGLEC1, HERC6, SLC1A2, OLAH 0.884 0.875 0.894 0.912 0.856 0.968 0.952 0.907 0.997 SIGLEC1, HERC6, IL1R2, MMP8 0.884 0.875 0.892 0.903 0.844 0.962 0.964 0.927 1 HERC6, IL1R2, FAM20A, RETN 0.884 0.874 0.893 0.907 0.846 0.967 0.926 0.840 1 SIGLEC1, FAM20A, RETN, MMP8 0.883 0.873 0.893 0.900 0.829 0.970 0.958 0.896 1 SIGLEC1, HERC6, FAM20A, RETN 0.883 0.873 0.893 0.898 0.827 0.968 0.955 0.890 1 SIGLEC1, SLC1A2, OLAH, RETN 0.883 0.874 0.892 0.913 0.857 0.969 0.949 0.899 0.998 SIGLEC1, ISG15, HERC6, IL1R2 0.883 0.874 0.891 0.902 0.841 0.963 0.953 0.909 0.998 SIGLEC1, FAM20A, OLAH, RETN 0.882 0.872 0.892 0.896 0.823 0.968 0.963 0.920 1 SIGLEC1, HERC6, IL1R2, OLAH 0.882 0.873 0.891 0.903 0.842 0.964 0.959 0.918 1,000 SIGLEC1, IL1R2, OLAH, MMP8 0.882 0.873 0.890 0.905 0.847 0.963 0.963 0.925 1 HERC6, SLC1A2, IL1R2, FAM20A 0.881 0.872 0.891 0.912 0.860 0.965 0.916 0.818 1 SIGLEC1, SLC1A2, IL1R2, MMP8 0.881 0.873 0.889 0.910 0.855 0.964 0.966 0.930 1 SIGLEC1, ISG15, SLC1A2, IL1R2 0.881 0.873 0.889 0.908 0.853 0.964 0.964 0.927 1 SIGLEC1, HERC6, SLC1A2, IL1R2 0.881 0.873 0.890 0.908 0.853 0.963 0.961 0.922 1 SIGLEC1, SLC1A2, IL1R2, RETN 0.881 0.873 0.889 0.910 0.855 0.965 0.962 0.922 1 HERC6, SLC1A2, FAM20A, OLAH 0.881 0.871 0.890 0.911 0.856 0.967 0.929 0.849 1 SIGLEC1, ISG15, FAM20A, RETN 0.881 0.871 0.890 0.893 0.821 0.966 0.954 0.895 1 SIGLEC1, ISG15, IL1R2, MMP8 0.881 0.873 0.889 0.903 0.844 0.962 0.962 0.923 1 SIGLEC1, SLC1A2, FAM20A, MMP8 0.880 0.870 0.890 0.902 0.838 0.966 0.951 0.877 1 SIGLEC1, ISG15, IL1R2, OLAH 0.880 0.872 0.888 0.902 0.841 0.963 0.961 0.920 1 SIGLEC1, ISG15, SLC1A2, FAM20A 0.880 0.871 0.889 0.901 0.837 0.965 0.949 0.877 1 SIGLEC1, HERC6, IL1R2, RETN 0.880 0.870 0.889 0.897 0.831 0.964 0.960 0.919 1 SIGLEC1, SLC1A2, FAM20A, RETN 0.880 0.870 0.889 0.902 0.838 0.966 0.948 0.875 1 SIGLEC1, HERC6, SLC1A2, FAM20A 0.880 0.870 0.889 0.901 0.837 0.964 0.954 0.881 1 HERC6, FAM20A, OLAH, RETN 0.879 0.870 0.889 0.903 0.839 0.967 0.945 0.879 1 SIGLEC1, IL1R2, RETN, MMP8 0.879 0.870 0.888 0.899 0.835 0.963 0.968 0.935 1 HERC6, FAM20A, OLAH, MMP8 0.879 0.869 0.889 0.899 0.835 0.963 0.942 0.875 1 ISG15, HERC6, FAM20A, OLAH 0.879 0.869 0.888 0.899 0.835 0.964 0.946 0.881 1 ISG15, SLC1A2, IL1R2, FAM20A 0.879 0.870 0.887 0.905 0.849 0.962 0.916 0.826 1 SIGLEC1, ISG15, HERC6, FAM20A 0.878 0.868 0.888 0.892 0.820 0.964 0.952 0.879 1 ISG15, IL1R2, FAM20A, OLAH 0.878 0.869 0.887 0.901 0.839 0.963 0.927 0.851 1 SIGLEC1, ISG15, FAM20A, MMP8 0.878 0.868 0.888 0.889 0.816 0.963 0.958 0.896 1 SIGLEC1, ISG15, IL1R2, RETN 0.878 0.869 0.886 0.898 0.833 0.963 0.965 0.926 1 SIGLEC1, IL1R2, OLAH, RETN 0.878 0.869 0.887 0.898 0.833 0.963 0.960 0.918 1 SIGLEC1, HERC6, FAM20A, MMP8 0.877 0.867 0.887 0.893 0.821 0.965 0.952 0.879 1 ISG15, HERC6, FAM20A, RETN 0.875 0.865 0.885 0.895 0.827 0.964 0.942 0.867 1 ISG15, IL1R2, FAM20A, MMP8 0.875 0.866 0.883 0.901 0.842 0.959 0.917 0.831 1 ISG15, HERC6, IL1R2, RETN 0.874 0.865 0.884 0.896 0.832 0.960 0.948 0.898 0.997 ISG15, SLC1A2, FAM20A, OLAH 0.874 0.865 0.883 0.901 0.842 0.961 0.912 0.830 0.994 SIGLEC1, HERC6, OLAH, MMP8 0.874 0.864 0.884 0.893 0.826 0.961 0.957 0.914 0.999 ISG15, HERC6, IL1R2, MMP8 0.874 0.865 0.883 0.897 0.838 0.955 0.941 0.889 0.994 ISG15, HERC6, IL1R2, OLAH 0.874 0.865 0.883 0.899 0.838 0.959 0.943 0.893 0.994 SIGLEC1, HERC6, OLAH, RETN 0.874 0.864 0.884 0.893 0.821 0.964 0.957 0.914 0.999 ISG15, HERC6, SLC1A2, OLAH 0.874 0.864 0.883 0.902 0.844 0.960 0.940 0.886 0.995 ISG15, IL1R2, FAM20A, RETN 0.873 0.864 0.882 0.900 0.838 0.961 0.925 0.842 1 SIGLEC1, OLAH, RETN, MMP8 0.873 0.863 0.883 0.892 0.821 0.962 0.964 0.925 1 HERC6, SLC1A2, IL1R2, OLAH 0.873 0.864 0.881 0.902 0.845 0.959 0.932 0.869 0.994 HERC6, SLC1A2, OLAH, MMP8 0.872 0.863 0.882 0.902 0.844 0.960 0.936 0.878 0.993 SIGLEC1, ISG15, HERC6, OLAH 0.872 0.863 0.881 0.891 0.822 0.960 0.954 0.911 0.998 ISG15, HERC6, SLC1A2, IL1R2 0.872 0.863 0.881 0.901 0.846 0.957 0.936 0.871 1 HERC6, SLC1A2, OLAH, RETN 0.872 0.862 0.881 0.903 0.844 0.962 0.935 0.874 0.995 ISG15, SLC1A2, IL1R2, OLAH 0.872 0.863 0.880 0.897 0.839 0.956 0.921 0.847 0.994 HERC6, IL1R2, OLAH, RETN 0.871 0.862 0.881 0.896 0.832 0.961 0.940 0.887 0.993 HERC6, IL1R2, OLAH, MMP8 0.871 0.862 0.880 0.897 0.838 0.956 0.935 0.877 0.992 HERC6, IL1R2, RETN, MMP8 0.871 0.862 0.881 0.893 0.828 0.958 0.930 0.867 0.994 SIGLEC1, ISG15, OLAH, MMP8 0.871 0.861 0.880 0.890 0.822 0.958 0.953 0.908 0.999 SIGLEC1, ISG15, OLAH, RETN 0.871 0.861 0.880 0.891 0.820 0.962 0.949 0.897 1 ISG15, HERC6, OLAH, RETN 0.870 0.860 0.880 0.892 0.822 0.962 0.953 0.909 0.998 HERC6, SLC1A2, IL1R2, RETN 0.869 0.860 0.879 0.899 0.841 0.958 0.915 0.839 0.992 HERC6, SLC1A2, FAM20A, RETN 0.869 0.859 0.879 0.896 0.833 0.960 0.934 0.851 1 HERC6, OLAH, RETN, MMP8 0.869 0.859 0.879 0.892 0.822 0.962 0.957 0.915 0.998 HERC6, SLC1A2, IL1R2, MMP8 0.869 0.860 0.878 0.900 0.845 0.955 0.910 0.828 0.991 SIGLEC1, HERC6, SLC1A2, RETN 0.868 0.858 0.877 0.893 0.827 0.960 0.955 0.910 1 ISG15, SLC1A2, OLAH, MMP8 0.868 0.858 0.877 0.894 0.835 0.954 0.922 0.856 0.988 ISG15, SLC1A2, OLAH, RETN 0.868 0.858 0.877 0.897 0.838 0.956 0.924 0.856 0.992 SIGLEC1, ISG15, HERC6, RETN 0.866 0.856 0.877 0.879 0.801 0.958 0.959 0.916 1 ISG15, SLC1A2, IL1R2, RETN 0.866 0.857 0.874 0.898 0.840 0.956 0.915 0.834 0.996 ISG15, HERC6, OLAH, MMP8 0.866 0.856 0.875 0.888 0.820 0.955 0.946 0.897 0.994 HERC6, FAM20A, RETN, MMP8 0.865 0.855 0.876 0.888 0.817 0.959 0.941 0.864 1 SIGLEC1, ISG15, SLC1A2, RETN 0.865 0.856 0.874 0.893 0.830 0.957 0.951 0.903 0.999 SIGLEC1, HERC6, RETN, MMP8 0.864 0.854 0.874 0.879 0.799 0.958 0.955 0.911 0.999 ISG15, SLC1A2, IL1R2, MMP8 0.863 0.855 0.871 0.894 0.837 0.951 0.917 0.837 0.998 ISG15, IL1R2, OLAH, MMP8 0.863 0.854 0.872 0.889 0.830 0.949 0.938 0.877 0.999 SIGLEC1, HERC6, SLC1A2, MMP8 0.863 0.854 0.872 0.887 0.822 0.952 0.934 0.877 0.991 HERC6, SLC1A2, FAM20A, MMP8 0.863 0.853 0.873 0.888 0.824 0.952 0.922 0.836 1 ISG15, IL1R2, OLAH, RETN 0.862 0.853 0.871 0.889 0.826 0.953 0.940 0.878 1 SIGLEC1, SLC1A2, RETN, MMP8 0.862 0.852 0.871 0.892 0.828 0.957 0.951 0.904 0.998 ISG15, HERC6, SLC1A2, FAM20A 0.862 0.852 0.871 0.886 0.822 0.950 0.933 0.850 1 ISG15, HERC6, FAM20A, MMP8 0.861 0.850 0.871 0.882 0.812 0.953 0.929 0.848 1 ISG15, HERC6, SLC1A2, RETN 0.860 0.851 0.870 0.886 0.819 0.954 0.940 0.877 1 ISG15, IL1R2, RETN, MMP8 0.860 0.851 0.869 0.888 0.825 0.950 0.935 0.871 0.999 SIGLEC1, ISG15, SLC1A2, MMP8 0.860 0.851 0.869 0.884 0.818 0.949 0.936 0.881 0.991 SLC1A2, IL1R2, FAM20A, OLAH 0.859 0.850 0.869 0.887 0.827 0.947 0.858 0.752 0.963 ISG15, FAM20A, OLAH, MMP8 0.859 0.850 0.869 0.886 0.820 0.952 0.947 0.894 0.999 SLC1A2, FAM20A, OLAH, MMP8 0.859 0.849 0.869 0.890 0.832 0.949 0.873 0.777 0.969 ISG15, FAM20A, OLAH, RETN 0.859 0.849 0.868 0.887 0.819 0.955 0.945 0.891 0.998 ISG15, HERC6, RETN, MMP8 0.857 0.847 0.868 0.877 0.801 0.954 0.945 0.893 0.996 SIGLEC1, ISG15, RETN, MMP8 0.857 0.847 0.867 0.874 0.797 0.952 0.958 0.914 1 SLC1A2, FAM20A, OLAH, RETN 0.856 0.846 0.866 0.883 0.821 0.945 0.862 0.759 0.965 SIGLEC1, ISG15, HERC6, SLC1A2 0.854 0.846 0.863 0.880 0.814 0.946 0.950 0.901 0.999 ISG15, OLAH, RETN, MMP8 0.853 0.843 0.863 0.879 0.811 0.948 0.957 0.912 1 HERC6, SLC1A2, RETN, MMP8 0.853 0.843 0.863 0.882 0.814 0.950 0.923 0.853 0.993 ISG15, HERC6, SLC1A2, MMP8 0.852 0.843 0.861 0.881 0.814 0.947 0.905 0.828 0.983 SLC1A2, IL1R2, OLAH, RETN 0.852 0.843 0.861 0.879 0.818 0.941 0.840 0.729 0.951 SIGLEC1, ISG15, HERC6, MMP8 0.852 0.842 0.862 0.871 0.795 0.946 0.915 0.849 0.981 SLC1A2, IL1R2, OLAH, MMP8 0.852 0.843 0.861 0.879 0.818 0.940 0.850 0.745 0.955 ISG15, SLC1A2, FAM20A, RETN 0.851 0.841 0.861 0.880 0.812 0.948 0.921 0.837 1 SLC1A2, OLAH, RETN, MMP8 0.850 0.840 0.860 0.881 0.819 0.942 0.858 0.757 0.958 IL1R2, FAM20A, OLAH, MMP8 0.848 0.838 0.857 0.878 0.818 0.938 0.871 0.773 0.968 ISG15, SLC1A2, FAM20A, MMP8 0.845 0.835 0.855 0.875 0.806 0.944 0.914 0.826 1 IL1R2, FAM20A, OLAH, RETN 0.840 0.830 0.850 0.870 0.805 0.935 0.864 0.763 0.965 ISG15, FAM20A, RETN, MMP8 0.839 0.829 0.849 0.868 0.799 0.938 0.936 0.865 1 SLC1A2, IL1R2, FAM20A, MMP8 0.835 0.827 0.844 0.868 0.806 0.930 0.855 0.741 0.970 SLC1A2, IL1R2, FAM20A, RETN 0.834 0.825 0.844 0.866 0.802 0.929 0.847 0.730 0.964 ISG15, SLC1A2, RETN, MMP8 0.832 0.823 0.842 0.865 0.796 0.934 0.921 0.851 0.990 IL1R2, OLAH, RETN, MMP8 0.832 0.822 0.842 0.866 0.803 0.930 0.861 0.761 0.960 FAM20A, OLAH, RETN, MMP8 0.830 0.820 0.841 0.863 0.797 0.929 0.877 0.786 0.968 IL1R2, FAM20A, RETN, MMP8 0.824 0.815 0.833 0.863 0.798 0.928 0.854 0.746 0.963 SLC1A2, IL1R2, RETN, MMP8 0.821 0.812 0.829 0.854 0.788 0.921 0.823 0.705 0.940

Performance obtained for identifying the viral or bacterial nature of the infection based on 5-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1, HERC6, IL1R2, FAM20A, MMP8 0.897 0.888 0.905 0.917 0.858 0.976 0.961 0.900 1 SIGLEC1, IL1R2, FAM20A, OLAH, MMP8 0.896 0.888 0.905 0.918 0.859 0.976 0.964 0.909 1 SIGLEC1, ISG15, IL1R2, FAM20A, MMP8 0.896 0.887 0.904 0.915 0.855 0.974 0.961 0.900 1 SIGLEC1, IL1R2, FAM20A, RETN, MMP8 0.894 0.885 0.903 0.917 0.858 0.976 0.961 0.901 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, MMP8 0.893 0.884 0.902 0.922 0.872 0.972 0.957 0.887 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A 0.889 0.880 0.898 0.912 0.850 0.974 0.959 0.900 1 SIGLEC1, HERC6, IL1R2, FAM20A, OLAH 0.889 0.880 0.898 0.911 0.848 0.974 0.959 0.900 1 SIGLEC1, SLC1A2, FAM20A, OLAH, MMP8 0.889 0.879 0.898 0.919 0.863 0.974 0.951 0.888 1 SIGLEC1, ISG15, IL1R2, FAM20A, OLAH 0.887 0.878 0.895 0.908 0.845 0.972 0.963 0.912 1 SIGLEC1, ISG15, IL1R2, FAM20A, RETN 0.886 0.877 0.895 0.906 0.842 0.971 0.962 0.907 1 SIGLEC1, HERC6, IL1R2, FAM20A, RETN 0.886 0.877 0.895 0.911 0.848 0.973 0.959 0.898 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A 0.886 0.876 0.895 0.917 0.864 0.971 0.948 0.875 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, OLAH 0.885 0.877 0.894 0.915 0.860 0.970 0.954 0.893 1 SIGLEC1, IL1R2, FAM20A, OLAH, RETN 0.885 0.876 0.894 0.907 0.843 0.971 0.962 0.907 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, RETN 0.885 0.876 0.894 0.916 0.862 0.969 0.953 0.885 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A 0.885 0.876 0.893 0.914 0.859 0.969 0.953 0.888 1 SIGLEC1, ISG15, SLC1A2, FAM20A, OLAH 0.884 0.874 0.893 0.913 0.854 0.971 0.950 0.891 1 SIGLEC1, HERC6, SLC1A2, FAM20A, OLAH 0.883 0.874 0.893 0.914 0.857 0.972 0.947 0.874 1 SIGLEC1, HERC6, FAM20A, OLAH, MMP8 0.883 0.872 0.893 0.902 0.835 0.970 0.963 0.914 1 SIGLEC1, FAM20A, OLAH, RETN, MMP8 0.882 0.872 0.893 0.905 0.838 0.973 0.970 0.929 1 SIGLEC1, ISG15, FAM20A, OLAH, MMP8 0.882 0.873 0.892 0.902 0.834 0.970 0.963 0.919 1 ISG15, HERC6, IL1R2, FAM20A, OLAH 0.882 0.873 0.892 0.906 0.846 0.966 0.935 0.858 1 SIGLEC1, SLC1A2, FAM20A, OLAH, RETN 0.882 0.873 0.892 0.913 0.854 0.972 0.950 0.890 1 ISG15, HERC6, IL1R2, FAM20A, MMP8 0.882 0.873 0.891 0.907 0.848 0.965 0.927 0.841 1 ISG15, HERC6, IL1R2, FAM20A, RETN 0.882 0.872 0.891 0.907 0.847 0.967 0.933 0.849 1 HERC6, IL1R2, FAM20A, OLAH, MMP8 0.881 0.872 0.890 0.908 0.851 0.965 0.932 0.851 1 SIGLEC1, ISG15, HERC6, FAM20A, OLAH 0.881 0.871 0.891 0.902 0.835 0.970 0.957 0.901 1 SIGLEC1, HERC6, FAM20A, RETN, MMP8 0.881 0.870 0.891 0.905 0.836 0.973 0.957 0.891 1 SIGLEC1, ISG15, SLC1A2, OLAH, MMP8 0.880 0.872 0.889 0.912 0.857 0.968 0.952 0.907 0.997 SIGLEC1, SLC1A2, IL1R2, OLAH, MMP8 0.880 0.872 0.889 0.912 0.858 0.967 0.966 0.931 1 SIGLEC1, ISG15, SLC1A2, IL1R2, OLAH 0.879 0.870 0.887 0.913 0.858 0.968 0.962 0.924 1 SIGLEC1, HERC6, FAM20A, OLAH, RETN 0.879 0.869 0.889 0.902 0.834 0.970 0.960 0.905 1 SIGLEC1, HERC6, SLC1A2, OLAH, MMP8 0.878 0.869 0.888 0.911 0.855 0.967 0.955 0.913 0.998 HERC6, IL1R2, FAM20A, OLAH, RETN 0.878 0.869 0.888 0.904 0.843 0.966 0.932 0.855 1 SIGLEC1, ISG15, HERC6, FAM20A, RETN 0.878 0.868 0.888 0.897 0.827 0.968 0.955 0.890 1 SIGLEC1, ISG15, FAM20A, RETN, MMP8 0.878 0.868 0.888 0.900 0.829 0.970 0.958 0.896 1 SIGLEC1, SLC1A2, IL1R2, OLAH, RETN 0.878 0.869 0.887 0.913 0.857 0.968 0.961 0.920 1 SIGLEC1, HERC6, IL1R2, OLAH, MMP8 0.878 0.869 0.887 0.905 0.846 0.964 0.966 0.931 1 SIGLEC1, HERC6, SLC1A2, IL1R2, OLAH 0.878 0.868 0.887 0.912 0.856 0.967 0.959 0.917 1 SIGLEC1, ISG15, HERC6, SLC1A2, OLAH 0.878 0.868 0.887 0.910 0.853 0.966 0.950 0.903 0.997 SIGLEC1, ISG15, HERC6, IL1R2, MMP8 0.877 0.869 0.886 0.903 0.844 0.963 0.964 0.927 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A 0.877 0.867 0.887 0.912 0.859 0.964 0.922 0.829 1 SIGLEC1, SLC1A2, FAM20A, RETN, MMP8 0.877 0.867 0.887 0.903 0.839 0.967 0.953 0.882 1 HERC6, SLC1A2, IL1R2, FAM20A, OLAH 0.877 0.868 0.886 0.914 0.861 0.967 0.922 0.835 1 SIGLEC1, ISG15, FAM20A, OLAH, RETN 0.877 0.867 0.887 0.896 0.825 0.968 0.962 0.919 1 SIGLEC1, ISG15, SLC1A2, OLAH, RETN 0.877 0.868 0.886 0.914 0.858 0.970 0.950 0.901 0.999 SIGLEC1, HERC6, IL1R2, RETN, MMP8 0.877 0.867 0.886 0.901 0.835 0.966 0.970 0.937 1 HERC6, IL1R2, FAM20A, RETN, MMP8 0.877 0.867 0.886 0.905 0.844 0.967 0.925 0.836 1 SIGLEC1, HERC6, SLC1A2, IL1R2, MMP8 0.876 0.868 0.885 0.907 0.852 0.962 0.963 0.925 1 SIGLEC1, SLC1A2, OLAH, RETN, MMP8 0.876 0.866 0.885 0.909 0.851 0.967 0.962 0.923 1 ISG15, SLC1A2, IL1R2, FAM20A, OLAH 0.876 0.866 0.885 0.908 0.850 0.965 0.924 0.844 1 SIGLEC1, HERC6, SLC1A2, FAM20A, RETN 0.875 0.865 0.886 0.903 0.839 0.966 0.950 0.876 1 SIGLEC1, ISG15, HERC6, IL1R2, OLAH 0.875 0.866 0.885 0.903 0.842 0.964 0.959 0.918 1,000 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2 0.875 0.867 0.884 0.908 0.853 0.963 0.962 0.923 1 ISG15, HERC6, SLC1A2, FAM20A, OLAH 0.875 0.866 0.885 0.911 0.855 0.967 0.932 0.852 1 SIGLEC1, ISG15, SLC1A2, IL1R2, MMP8 0.875 0.868 0.883 0.910 0.856 0.964 0.966 0.930 1 SIGLEC1, ISG15, IL1R2, OLAH, MMP8 0.875 0.867 0.884 0.905 0.847 0.963 0.963 0.925 1 SIGLEC1, ISG15, SLC1A2, FAM20A, MMP8 0.875 0.865 0.885 0.900 0.836 0.964 0.952 0.880 1 HERC6, SLC1A2, FAM20A, OLAH, MMP8 0.875 0.866 0.885 0.911 0.856 0.966 0.928 0.846 1 SIGLEC1, ISG15, SLC1A2, IL1R2, RETN 0.875 0.867 0.883 0.909 0.854 0.964 0.965 0.927 1 SIGLEC1, ISG15, SLC1A2, FAM20A, RETN 0.875 0.865 0.885 0.902 0.839 0.966 0.948 0.875 1 SIGLEC1, HERC6, SLC1A2, IL1R2, RETN 0.875 0.866 0.884 0.909 0.853 0.965 0.960 0.919 1 HERC6, SLC1A2, IL1R2, FAM20A, RETN 0.875 0.865 0.884 0.912 0.858 0.966 0.918 0.824 1 SIGLEC1, HERC6, SLC1A2, OLAH, RETN 0.875 0.865 0.885 0.910 0.851 0.968 0.958 0.915 1,000 SIGLEC1, SLC1A2, IL1R2, RETN, MMP8 0.875 0.866 0.883 0.912 0.858 0.966 0.968 0.935 1 SIGLEC1, ISG15, IL1R2, RETN, MMP8 0.874 0.865 0.883 0.901 0.837 0.964 0.971 0.938 1 SIGLEC1, HERC6, SLC1A2, FAM20A, MMP8 0.874 0.864 0.884 0.901 0.838 0.964 0.954 0.881 1 HERC6, SLC1A2, IL1R2, FAM20A, MMP8 0.874 0.865 0.883 0.913 0.862 0.964 0.917 0.819 1 HERC6, FAM20A, OLAH, RETN, MMP8 0.874 0.864 0.884 0.900 0.835 0.965 0.949 0.885 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A 0.874 0.864 0.884 0.901 0.838 0.964 0.952 0.879 1 HERC6, SLC1A2, FAM20A, OLAH, RETN 0.874 0.864 0.884 0.910 0.854 0.966 0.928 0.847 1 ISG15, HERC6, FAM20A, OLAH, RETN 0.874 0.864 0.883 0.899 0.833 0.965 0.950 0.887 1 SIGLEC1, IL1R2, OLAH, RETN, MMP8 0.873 0.864 0.883 0.901 0.838 0.964 0.968 0.935 1 SIGLEC1, ISG15, HERC6, IL1R2, RETN 0.873 0.864 0.883 0.898 0.831 0.964 0.962 0.923 1 SIGLEC1, HERC6, IL1R2, OLAH, RETN 0.873 0.863 0.883 0.900 0.835 0.966 0.960 0.919 1 ISG15, HERC6, FAM20A, OLAH, MMP8 0.873 0.863 0.883 0.899 0.834 0.963 0.945 0.878 1 SIGLEC1, ISG15, HERC6, FAM20A, MMP8 0.872 0.861 0.882 0.891 0.819 0.963 0.952 0.881 1 SIGLEC1, ISG15, IL1R2, OLAH, RETN 0.871 0.862 0.880 0.900 0.836 0.964 0.964 0.924 1 SIGLEC1, HERC6, OLAH, RETN, MMP8 0.871 0.861 0.882 0.892 0.820 0.965 0.961 0.922 1,000 ISG15, IL1R2, FAM20A, OLAH, MMP8 0.870 0.861 0.879 0.900 0.840 0.960 0.930 0.855 1 ISG15, SLC1A2, IL1R2, FAM20A, RETN 0.869 0.860 0.879 0.906 0.850 0.963 0.916 0.826 1 ISG15, HERC6, IL1R2, RETN, MMP8 0.869 0.859 0.878 0.897 0.833 0.960 0.948 0.895 1 ISG15, SLC1A2, IL1R2, FAM20A, MMP8 0.869 0.860 0.877 0.906 0.852 0.961 0.914 0.822 1 SIGLEC1, ISG15, HERC6, OLAH, RETN 0.868 0.858 0.879 0.892 0.820 0.964 0.957 0.914 0.999 ISG15, HERC6, SLC1A2, IL1R2, OLAH 0.868 0.859 0.877 0.904 0.848 0.961 0.936 0.878 0.994 ISG15, HERC6, SLC1A2, OLAH, MMP8 0.868 0.858 0.877 0.903 0.845 0.960 0.940 0.886 0.995 ISG15, HERC6, SLC1A2, FAM20A, RETN 0.868 0.858 0.878 0.899 0.835 0.963 0.940 0.860 1 SIGLEC1, ISG15, HERC6, OLAH, MMP8 0.868 0.858 0.877 0.891 0.823 0.959 0.954 0.911 0.998 ISG15, HERC6, SLC1A2, OLAH, RETN 0.867 0.858 0.877 0.903 0.844 0.963 0.943 0.888 0.999 SIGLEC1, ISG15, OLAH, RETN, MMP8 0.867 0.857 0.877 0.891 0.820 0.961 0.964 0.925 1 ISG15, IL1R2, FAM20A, OLAH, RETN 0.867 0.857 0.877 0.901 0.839 0.962 0.927 0.851 1 ISG15, SLC1A2, FAM20A, OLAH, MMP8 0.867 0.857 0.877 0.901 0.843 0.960 0.921 0.842 0.999 HERC6, SLC1A2, IL1R2, OLAH, RETN 0.867 0.858 0.876 0.904 0.846 0.961 0.932 0.867 0.996 ISG15, HERC6, IL1R2, OLAH, MMP8 0.867 0.857 0.876 0.900 0.840 0.959 0.949 0.902 0.996 ISG15, HERC6, IL1R2, OLAH, RETN 0.867 0.857 0.877 0.899 0.835 0.963 0.951 0.905 0.997 ISG15, IL1R2, FAM20A, RETN, MMP8 0.866 0.858 0.875 0.901 0.842 0.960 0.921 0.836 1 HERC6, IL1R2, OLAH, RETN, MMP8 0.866 0.856 0.877 0.899 0.836 0.962 0.953 0.909 0.997 HERC6, SLC1A2, OLAH, RETN, MMP8 0.866 0.857 0.876 0.902 0.842 0.962 0.943 0.890 0.997 ISG15, HERC6, SLC1A2, IL1R2, RETN 0.866 0.857 0.876 0.901 0.843 0.959 0.936 0.871 1 HERC6, SLC1A2, IL1R2, OLAH, MMP8 0.866 0.857 0.875 0.901 0.844 0.958 0.935 0.874 0.995 ISG15, HERC6, FAM20A, RETN, MMP8 0.866 0.855 0.876 0.895 0.826 0.963 0.942 0.869 1 ISG15, HERC6, SLC1A2, IL1R2, MMP8 0.865 0.856 0.874 0.901 0.845 0.956 0.932 0.866 0.997 ISG15, SLC1A2, FAM20A, OLAH, RETN 0.865 0.855 0.875 0.903 0.844 0.962 0.913 0.831 0.995 ISG15, HERC6, OLAH, RETN, MMP8 0.865 0.854 0.875 0.892 0.822 0.962 0.961 0.922 1,000 ISG15, SLC1A2, IL1R2, OLAH, RETN 0.864 0.855 0.873 0.899 0.840 0.957 0.921 0.846 0.995 ISG15, SLC1A2, IL1R2, OLAH, MMP8 0.863 0.854 0.872 0.896 0.838 0.954 0.926 0.856 0.997 SIGLEC1, ISG15, HERC6, SLC1A2, RETN 0.862 0.853 0.872 0.893 0.826 0.960 0.960 0.916 1 HERC6, SLC1A2, IL1R2, RETN, MMP8 0.862 0.853 0.872 0.899 0.841 0.957 0.922 0.847 0.997 HERC6, SLC1A2, FAM20A, RETN, MMP8 0.861 0.851 0.871 0.896 0.832 0.960 0.936 0.854 1 SIGLEC1, HERC6, SLC1A2, RETN, MMP8 0.861 0.851 0.870 0.893 0.827 0.960 0.955 0.910 1 SIGLEC1, ISG15, HERC6, RETN, MMP8 0.859 0.849 0.870 0.879 0.800 0.958 0.959 0.916 1 ISG15, HERC6, SLC1A2, FAM20A, MMP8 0.859 0.848 0.869 0.890 0.826 0.955 0.925 0.840 1 ISG15, SLC1A2, OLAH, RETN, MMP8 0.858 0.849 0.868 0.898 0.839 0.957 0.935 0.873 0.996 SIGLEC1, ISG15, SLC1A2, RETN, MMP8 0.856 0.847 0.866 0.893 0.829 0.958 0.953 0.906 1 SIGLEC1, ISG15, HERC6, SLC1A2, MMP8 0.856 0.847 0.865 0.887 0.822 0.952 0.934 0.877 0.991 ISG15, SLC1A2, IL1R2, RETN, MMP8 0.856 0.847 0.865 0.897 0.840 0.954 0.918 0.838 0.999 ISG15, IL1R2, OLAH, RETN, MMP8 0.855 0.846 0.865 0.892 0.830 0.954 0.943 0.886 1 ISG15, FAM20A, OLAH, RETN, MMP8 0.854 0.844 0.865 0.891 0.826 0.956 0.950 0.899 1 SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.854 0.845 0.864 0.891 0.835 0.947 0.877 0.782 0.973 ISG15, HERC6, SLC1A2, RETN, MMP8 0.853 0.843 0.863 0.886 0.818 0.954 0.935 0.870 0.999 SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.852 0.843 0.862 0.884 0.823 0.945 0.862 0.759 0.965 SLC1A2, FAM20A, OLAH, RETN, MMP8 0.850 0.840 0.860 0.891 0.833 0.949 0.874 0.778 0.970 SLC1A2, IL1R2, OLAH, RETN, MMP8 0.844 0.835 0.853 0.879 0.818 0.939 0.852 0.746 0.958 ISG15, SLC1A2, FAM20A, RETN, MMP8 0.842 0.832 0.853 0.881 0.813 0.949 0.918 0.834 1 IL1R2, FAM20A, OLAH, RETN, MMP8 0.837 0.827 0.846 0.877 0.816 0.938 0.871 0.773 0.968 SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.827 0.818 0.836 0.869 0.807 0.931 0.857 0.742 0.971

Performance obtained for identifying the viral or bacterial nature of the infection based on 6-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1, ISG15, IL1R2, FAM20A, OLAH, MMP8 0.891 0.883 0.900 0.916 0.857 0.974 0.964 0.909 1 SIGLEC1, HERC6, IL1R2, FAM20A, OLAH, MMP8 0.891 0.882 0.900 0.918 0.859 0.976 0.964 0.909 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, MMP8 0.891 0.882 0.900 0.915 0.855 0.974 0.962 0.903 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.888 0.879 0.897 0.922 0.872 0.972 0.957 0.890 1 SIGLEC1, HERC6, IL1R2, FAM20A, RETN, MMP8 0.888 0.878 0.897 0.918 0.859 0.976 0.960 0.898 1 SIGLEC1, ISG15, IL1R2, FAM20A, RETN, MMP8 0.888 0.879 0.896 0.915 0.855 0.975 0.962 0.902 1 SIGLEC1, IL1R2, FAM20A, OLAH, RETN, MMP8 0.887 0.878 0.897 0.918 0.860 0.977 0.963 0.909 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, MMP8 0.887 0.879 0.896 0.924 0.877 0.972 0.958 0.890 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, MMP8 0.887 0.878 0.897 0.923 0.873 0.973 0.959 0.893 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.886 0.876 0.895 0.922 0.872 0.973 0.957 0.887 1 SIGLEC1, ISG15, SLC1A2, FAM20A, OLAH, MMP8 0.884 0.874 0.893 0.916 0.860 0.971 0.951 0.889 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, OLAH 0.883 0.874 0.893 0.911 0.849 0.974 0.958 0.899 1 SIGLEC1, HERC6, SLC1A2, FAM20A, OLAH, MMP8 0.882 0.872 0.892 0.918 0.863 0.973 0.951 0.883 1 SIGLEC1, ISG15, IL1R2, FAM20A, OLAH, RETN 0.881 0.872 0.890 0.906 0.841 0.970 0.963 0.910 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, OLAH 0.881 0.871 0.890 0.919 0.865 0.972 0.947 0.874 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.880 0.871 0.889 0.916 0.863 0.970 0.957 0.896 1 SIGLEC1, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.880 0.870 0.890 0.916 0.858 0.973 0.948 0.879 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH 0.880 0.871 0.889 0.915 0.861 0.970 0.954 0.893 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, RETN 0.880 0.870 0.889 0.910 0.848 0.972 0.959 0.898 1 SIGLEC1, HERC6, IL1R2, FAM20A, OLAH, RETN 0.880 0.870 0.889 0.910 0.846 0.973 0.960 0.901 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A 0.879 0.870 0.889 0.919 0.866 0.972 0.949 0.876 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, RETN 0.879 0.870 0.888 0.915 0.862 0.969 0.953 0.885 1 SIGLEC1, HERC6, FAM20A, OLAH, RETN, MMP8 0.878 0.868 0.889 0.909 0.842 0.975 0.963 0.910 1 SIGLEC1, ISG15, HERC6, FAM20A, OLAH, MMP8 0.878 0.868 0.888 0.903 0.835 0.970 0.964 0.916 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, OLAH 0.878 0.868 0.888 0.914 0.857 0.970 0.946 0.872 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, RETN 0.878 0.868 0.887 0.918 0.865 0.971 0.948 0.875 1 SIGLEC1, ISG15, FAM20A, OLAH, RETN, MMP8 0.877 0.867 0.887 0.904 0.837 0.972 0.970 0.929 1 SIGLEC1, ISG15, SLC1A2, FAM20A, OLAH, RETN 0.877 0.867 0.886 0.914 0.856 0.971 0.949 0.887 1 ISG15, HERC6, IL1R2, FAM20A, OLAH, MMP8 0.876 0.867 0.886 0.908 0.850 0.966 0.935 0.855 1 SIGLEC1, ISG15, HERC6, FAM20A, RETN, MMP8 0.875 0.865 0.886 0.904 0.835 0.972 0.957 0.891 1 ISG15, HERC6, IL1R2, FAM20A, RETN, MMP8 0.875 0.866 0.885 0.910 0.850 0.969 0.932 0.848 1 SIGLEC1, HERC6, SLC1A2, FAM20A, OLAH, RETN 0.875 0.864 0.885 0.914 0.856 0.971 0.947 0.874 1 ISG15, HERC6, IL1R2, FAM20A, OLAH, RETN 0.874 0.865 0.884 0.906 0.845 0.967 0.937 0.862 1 SIGLEC1, ISG15, HERC6, FAM20A, OLAH, RETN 0.874 0.864 0.884 0.900 0.833 0.968 0.958 0.902 1 SIGLEC1, ISG15, SLC1A2, IL1R2, OLAH, MMP8 0.874 0.866 0.883 0.913 0.859 0.966 0.965 0.929 1 SIGLEC1, HERC6, SLC1A2, IL1R2, OLAH, MMP8 0.874 0.864 0.883 0.911 0.857 0.966 0.965 0.929 1 SIGLEC1, ISG15, HERC6, SLC1A2, OLAH, MMP8 0.873 0.863 0.882 0.910 0.853 0.966 0.951 0.905 0.997 HERC6, IL1R2, FAM20A, OLAH, RETN, MMP8 0.873 0.863 0.883 0.909 0.850 0.968 0.939 0.862 1 SIGLEC1, HERC6, SLC1A2, FAM20A, RETN, MMP8 0.873 0.863 0.883 0.904 0.840 0.968 0.953 0.880 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH 0.873 0.863 0.883 0.911 0.857 0.966 0.926 0.842 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH 0.872 0.863 0.881 0.912 0.857 0.966 0.957 0.914 0.999 SIGLEC1, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.872 0.862 0.881 0.914 0.859 0.968 0.968 0.935 1 SIGLEC1, ISG15, SLC1A2, FAM20A, RETN, MMP8 0.872 0.862 0.882 0.903 0.840 0.967 0.953 0.882 1 SIGLEC1, ISG15, SLC1A2, IL1R2, OLAH, RETN 0.872 0.863 0.881 0.913 0.857 0.968 0.961 0.920 1 HERC6, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.872 0.862 0.881 0.912 0.861 0.964 0.921 0.830 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, RETN 0.871 0.861 0.881 0.901 0.838 0.965 0.950 0.876 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, RETN 0.871 0.861 0.881 0.912 0.858 0.966 0.926 0.837 1 SIGLEC1, ISG15, HERC6, IL1R2, RETN, MMP8 0.871 0.861 0.880 0.901 0.836 0.966 0.970 0.937 1 SIGLEC1, ISG15, SLC1A2, OLAH, RETN, MMP8 0.871 0.861 0.880 0.910 0.852 0.968 0.959 0.917 1,000 SIGLEC1, HERC6, IL1R2, OLAH, RETN, MMP8 0.871 0.861 0.881 0.901 0.836 0.965 0.968 0.935 1 SIGLEC1, ISG15, HERC6, IL1R2, OLAH, MMP8 0.871 0.861 0.880 0.904 0.845 0.963 0.964 0.927 1 SIGLEC1, HERC6, SLC1A2, OLAH, RETN, MMP8 0.871 0.860 0.881 0.909 0.850 0.968 0.964 0.927 1 HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.870 0.860 0.880 0.913 0.859 0.967 0.922 0.834 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, MMP8 0.870 0.860 0.880 0.915 0.864 0.966 0.921 0.824 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, MMP8 0.870 0.861 0.878 0.907 0.852 0.962 0.963 0.925 1 SIGLEC1, HERC6, SLC1A2, IL1R2, OLAH, RETN 0.870 0.860 0.880 0.914 0.860 0.969 0.959 0.917 1 ISG15, HERC6, FAM20A, OLAH, RETN, MMP8 0.869 0.859 0.880 0.903 0.838 0.968 0.951 0.888 1 SIGLEC1, ISG15, HERC6, SLC1A2, OLAH, RETN 0.869 0.859 0.879 0.909 0.850 0.967 0.954 0.910 0.999 SIGLEC1, HERC6, SLC1A2, IL1R2, RETN, MMP8 0.869 0.860 0.879 0.909 0.854 0.965 0.971 0.939 1 ISG15, HERC6, SLC1A2, FAM20A, OLAH, RETN 0.869 0.859 0.879 0.911 0.855 0.968 0.932 0.851 1 HERC6, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.869 0.859 0.879 0.911 0.854 0.967 0.934 0.855 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, MMP8 0.869 0.859 0.879 0.900 0.838 0.963 0.952 0.879 1 ISG15, HERC6, SLC1A2, FAM20A, OLAH, MMP8 0.869 0.859 0.879 0.912 0.857 0.966 0.929 0.847 1 SIGLEC1, ISG15, SLC1A2, IL1R2, RETN, MMP8 0.868 0.860 0.877 0.912 0.858 0.966 0.970 0.937 1 HERC6, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.868 0.859 0.878 0.913 0.860 0.966 0.924 0.831 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, RETN 0.868 0.859 0.877 0.909 0.853 0.965 0.960 0.919 1 SIGLEC1, ISG15, IL1R2, OLAH, RETN, MMP8 0.868 0.858 0.877 0.902 0.839 0.965 0.970 0.937 1 ISG15, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.867 0.858 0.876 0.910 0.856 0.964 0.923 0.840 1 SIGLEC1, ISG15, HERC6, IL1R2, OLAH, RETN 0.866 0.856 0.876 0.900 0.835 0.966 0.959 0.918 1,000 ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.866 0.857 0.876 0.908 0.851 0.965 0.924 0.844 1 SIGLEC1, ISG15, HERC6, OLAH, RETN, MMP8 0.865 0.854 0.875 0.892 0.819 0.964 0.961 0.922 1,000 ISG15, HERC6, IL1R2, OLAH, RETN, MMP8 0.862 0.852 0.872 0.900 0.837 0.964 0.961 0.922 1 ISG15, HERC6, SLC1A2, IL1R2, OLAH, RETN 0.861 0.852 0.871 0.907 0.851 0.964 0.941 0.884 0.999 ISG15, HERC6, SLC1A2, OLAH, RETN, MMP8 0.861 0.851 0.871 0.905 0.846 0.964 0.952 0.905 0.999 ISG15, HERC6, SLC1A2, IL1R2, OLAH, MMP8 0.861 0.852 0.870 0.904 0.848 0.961 0.940 0.885 0.996 HERC6, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.861 0.851 0.870 0.904 0.846 0.962 0.939 0.881 0.997 ISG15, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.860 0.851 0.869 0.906 0.851 0.961 0.916 0.826 1 ISG15, IL1R2, FAM20A, OLAH, RETN, MMP8 0.860 0.851 0.870 0.901 0.842 0.961 0.935 0.864 1 ISG15, HERC6, SLC1A2, FAM20A, RETN, MMP8 0.860 0.850 0.870 0.900 0.836 0.965 0.940 0.862 1 ISG15, HERC6, SLC1A2, IL1R2, RETN, MMP8 0.859 0.849 0.868 0.902 0.845 0.959 0.942 0.881 1 ISG15, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.859 0.849 0.869 0.904 0.848 0.961 0.923 0.847 0.999 SIGLEC1, ISG15, HERC6, SLC1A2, RETN, MMP8 0.855 0.845 0.865 0.893 0.826 0.960 0.960 0.916 1 ISG15, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.854 0.845 0.864 0.900 0.843 0.958 0.930 0.862 0.999 SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.846 0.836 0.855 0.891 0.835 0.947 0.876 0.780 0.972

Performance obtained for identifying the viral or bacterial nature of the infection based on 7-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, OLAH, MMP8 0.885 0.876 0.895 0.916 0.858 0.974 0.964 0.909 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.883 0.874 0.892 0.924 0.875 0.973 0.958 0.892 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.883 0.873 0.892 0.922 0.872 0.972 0.960 0.898 1 SIGLEC1, ISG15, IL1R2, FAM20A, OLAH, RETN, MMP8 0.882 0.873 0.892 0.915 0.855 0.975 0.965 0.911 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, RETN, MMP8 0.882 0.873 0.891 0.915 0.855 0.975 0.961 0.900 1 SIGLEC1, HERC6, IL1R2, FAM20A, OLAH, RETN, MMP8 0.881 0.871 0.891 0.918 0.859 0.976 0.965 0.911 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, MMP8 0.881 0.871 0.890 0.924 0.876 0.972 0.959 0.893 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.880 0.871 0.889 0.924 0.875 0.973 0.955 0.885 1 SIGLEC1, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.879 0.870 0.889 0.923 0.872 0.973 0.958 0.892 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.878 0.869 0.888 0.922 0.872 0.973 0.957 0.889 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, OLAH, MMP8 0.877 0.867 0.887 0.919 0.865 0.973 0.947 0.876 1 SIGLEC1, ISG15, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.876 0.866 0.886 0.915 0.858 0.972 0.949 0.882 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.875 0.865 0.884 0.918 0.865 0.970 0.955 0.894 1 SIGLEC1, HERC6, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.875 0.864 0.885 0.917 0.860 0.974 0.949 0.877 1 SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, OLAH, RETN 0.874 0.865 0.884 0.908 0.845 0.971 0.960 0.901 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH 0.874 0.864 0.884 0.917 0.863 0.971 0.948 0.875 1 SIGLEC1, ISG15, HERC6, FAM20A, OLAH, RETN, MMP8 0.874 0.863 0.884 0.907 0.840 0.975 0.962 0.910 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.873 0.862 0.883 0.918 0.864 0.971 0.947 0.874 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, RETN 0.872 0.861 0.882 0.918 0.866 0.970 0.950 0.878 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, OLAH, RETN 0.870 0.859 0.880 0.912 0.855 0.970 0.945 0.871 1 ISG15, HERC6, IL1R2, FAM20A, OLAH, RETN, MMP8 0.869 0.859 0.879 0.909 0.850 0.969 0.939 0.863 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, RETN, MMP8 0.867 0.857 0.878 0.904 0.840 0.968 0.953 0.880 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, MMP8 0.867 0.858 0.876 0.912 0.859 0.966 0.963 0.926 1 SIGLEC1, ISG15, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.866 0.857 0.875 0.912 0.857 0.967 0.966 0.931 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.866 0.856 0.875 0.917 0.864 0.970 0.927 0.838 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.866 0.856 0.875 0.915 0.865 0.966 0.926 0.839 1 SIGLEC1, HERC6, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.865 0.856 0.875 0.913 0.858 0.968 0.967 0.933 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.865 0.855 0.876 0.913 0.858 0.968 0.926 0.840 1 HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.865 0.855 0.875 0.914 0.862 0.967 0.925 0.838 1 SIGLEC1, ISG15, HERC6, IL1R2, OLAH, RETN, MMP8 0.864 0.855 0.874 0.901 0.836 0.965 0.968 0.935 1 SIGLEC1, ISG15, HERC6, SLC1A2, OLAH, RETN, MMP8 0.864 0.854 0.874 0.910 0.850 0.969 0.958 0.916 0.999 ISG15, HERC6, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.864 0.854 0.874 0.911 0.854 0.968 0.935 0.856 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, RETN 0.864 0.854 0.874 0.915 0.860 0.969 0.959 0.917 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, RETN, MMP8 0.863 0.854 0.872 0.909 0.853 0.965 0.970 0.937 1 ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.858 0.848 0.867 0.911 0.857 0.964 0.923 0.842 1 ISG15, HERC6, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.855 0.845 0.864 0.908 0.853 0.964 0.951 0.902 1

Performance obtained for identifying the viral or bacterial nature of the infection based on 8-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1, ISG15, HERC6, IL1R2, FAM20A, OLAH, RETN, MMP8 0.877 0.868 0.887 0.916 0.857 0.976 0.965 0.911 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, MMP8 0.876 0.867 0.886 0.924 0.876 0.973 0.959 0.895 1 SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.875 0.865 0.884 0.923 0.874 0.973 0.957 0.890 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, RETN, MMP8 0.873 0.864 0.883 0.925 0.876 0.974 0.955 0.885 1 SIGLEC1, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.872 0.862 0.883 0.923 0.872 0.973 0.958 0.892 1 SIGLEC1, ISG15, HERC6, SLC1A2, FAM20A, OLAH, RETN, MMP8 0.870 0.859 0.880 0.918 0.862 0.974 0.948 0.875 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN 0.866 0.856 0.876 0.918 0.865 0.971 0.948 0.875 1 ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN, MMP8 0.860 0.850 0.870 0.916 0.865 0.968 0.928 0.843 1 SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, RETN, MMP8 0.860 0.850 0.869 0.912 0.856 0.968 0.965 0.929 1

Performance obtained for identifying the viral or bacterial nature of the infection based on 9-gene combinations:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1 ISG15 HERC6 SLC1A2 IL1R2 FAM20A OLAH RETN MMP8 0.869 0.859 0.879 0.923 0.873 0.972 0.957 0.890 1

Performance obtained for identifying the viral or bacterial nature of the infection based on combinations of the nine target genes and additional genes:

Model AUC (model) 95% CI AUC (Train) 95% CI (Train) AUC (Test) 95% CI (Test) SIGLEC1 ISG15 HERC6 SLC1A2 IL1R2 FAM20A OLAH RETN MMP8 RSAD2, IFI27, OAS1, IFIT1, IFI44L, PI3, EBI3, ADGRE1 and S100P 0.814 0.797 0.831 0.959 0.925 0.993 0.928 0.861 0.995

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 set. TRAIN.

BIBLIOGRAPHICAL REFERENCES

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

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

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

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

Eric D. Brown et al. (2016), “Antibacterial drug discovery in the resistance era” - Review – doi:10.1038/nature17042.

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.

Claims (31)

In vitro or ex vivo method for determining the viral or bacterial nature of an infection from a biological sample from an infected subject, or likely to be infected, comprising the following steps:
(a) measurement of the expression at the mRNA level of at least two genes chosen from the target genes SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8,
(b) comparison of the expressions measured in step (a) with reference expression values of said target genes, said reference expression values corresponding either to the respective expression of said target genes in a reference biological sample obtained in a subject having a viral infection, or to the respective expression of said target genes in a reference biological sample obtained in a subject having a bacterial infection, and
(c) conclusion as to the viral or bacterial nature of the infection based on the comparison results. Method according to claim 1, characterized in that step (a) comprises measuring at least one target gene chosen from SIGLEC1, ISG15 and HERC6, and at least one other target gene chosen from SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8. Method according to claim 1, characterized in that step (a) comprises measuring the expression of the target gene SIGLEC1 and at least one other target gene chosen from ISG15, HERC6, SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, and more preferably from IL1R2, OLAH and FAM20A. Method according to claim 1, characterized in that step (a) comprises measuring the expression of the target gene HERC6 and at least one other target gene chosen from SIGLEC1, ISG15, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, preferably from SLC1A2, IL1R2, OLAH, FAM20A and RETN, more preferably from SLC1A2, IL1R2, OLAH and FAM20A. Method according to claim 1, characterized in that step (a) comprises 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 ; OLAH_MMP8 ; OLAH_RETN ; ISG15_HERC6 ; IL1R2_MMP8 ; IL1R2_RETN ; ISG15_MMP8 and ISG15_SLC1A2, and preferably chosen from the following combinations of genes: SIGLEC1_IL1R2; SIGLEC1_FAM20A ; HERC6_IL1R2; SIGLEC1_OLAH and HERC6_OLAH. Method according to claim 1, characterized in that step (a) comprises measuring the expression of three target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and preferably among SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, and OLAH. Method according to claim 6, characterized in that step (a) comprises the measurement of at least one target gene chosen from SIGLEC1, ISG15 and HERC6, and at least two target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN and MMP8, and preferably IL1R2, OLAH and FAM20A. Method according to claim 6, characterized in that step (a) comprises measuring the expression of the target genes SIGLEC1 and 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. Method according to claim 6, characterized in that step (a) comprises measuring the expression of a combination of three target genes chosen from the following combinations SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A, SIGLEC1_SLC1A2_OLAH, SIGLEC1_HERC6_IL1R2, SIGLEC1_FAM20A_OLAH, SIGLEC1_IL1R2_MMP8 , SIGLEC1_ISG15_IL1R2, SIGLEC1_SLC1A2_IL1R2, SIGLEC1_IL1R2_OLAH, SIGLEC1_SLC1A2_FAM20A and HERC6_FAM20A_OLAH, and more preferably from SIGLEC1_IL1R2_FAM20A, HERC6_IL1R2_FAM20A and SIGLEC1_SLC1A2_OLAH. Method according to claim 1, characterized in that step (a) comprises measuring the expression of four target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and preferably among SIGLEC1, SLC1A2, IL1R2, FAM20A, OLAH, and MMP8. Method according to claim 10, characterized in that step (a) comprises measuring the expression of at least two target genes chosen from SIGLEC1, ISG15 and HERC6, and of at least two target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A, RETN and MMP8, and preferably IL1R2, OLAH and FAM20A. Method according to claim 10, characterized in that step (a) comprises measuring the expression of the target gene SIGLEC1 and at least three target genes chosen from SLC1A2, IL1R2, OLAH, FAM20A and RETN. Method according to claim 10, characterized in that step (a) comprises measuring the expression of a combination of four target genes chosen from the following combinations: SIGLEC1_IL1R2_FAM20A_MMP8, SIGLEC1_HERC6_IL1R2_FAM20A, SIGLEC1_ISG15_IL1R2_FAM20A, SIGLEC1_IL1R2_FAM20A_OLAH, SIGLEC1 _IL1R2_FAM20A_RETN, SIGLEC1_SLC1A2_IL1R2_FAM20A, SIGLEC1_SLC1A2_FAM20A_OLAH , ISG15_HERC6_IL1R2_FAM20A, SIGLEC1_FAM20A_OLAH_MMP8, and HERC6_IL1R2_FAM20A_OLAH. Method according to claim 1, characterized in that step (a) comprises measuring the expression of five target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8, and preferably among SIGLEC1, HERC6, IL1R2, FAM20A, OLAH, RETN and MMP8. Method according to claim 14, characterized in that step (a) comprises 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. Method according to claim 14, characterized in that step (a) comprises measuring the expression of the target genes SIGLEC1 and MMP8 and at least three other target genes chosen from HERC6, ISG15, SLC1A2, OLAH, FAM20A, RETN and IL1R2, preferably from OLAH, SLC1A2, FAM20A and IL1R2. Method according to claim 14, characterized in that step (a) comprises measuring the expression of a combination of five target genes chosen from the following combinations:
- SIGLEC1_HERC6_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_OLAH_MMP8
- SIGLEC1_ISG15_IL1R2_FAM20A_MMP8
- SIGLEC1_IL1R2_FAM20A_RETN_MMP8
- SIGLEC1_SLC1A2_IL1R2_FAM20A_MMP8
- SIGLEC1_ISG15_HERC6_IL1R2_FAM20A
- SIGLEC1_HERC6_IL1R2_FAM20A_OLAH
- SIGLEC1_SLC1A2_FAM20A_OLAH_MMP8, and
- SIGLEC1_ISG15_IL1R2_FAM20A_OLAH. Method according to claim 1, characterized in that step (a) comprises measuring the expression of six target genes chosen from SIGLEC1, ISG15, HERC6, SLC1A2, IL1R2, FAM20A, OLAH, RETN and MMP8. Method according to claim 18, characterized in that step (a) comprises measuring the expression of the target genes SIGLEC1 and MMP8, and at least four other target genes chosen from HERC6, ISG15, IL1R2, SLC1A2, OLAH , FAM20A and RETN. Method according to claim 18, characterized in that step (a) comprises measuring the expression of target genes SIGLEC1, FAM20A and MMP8 and at least three other target genes chosen from ISG15, HERC6, IL1R2, SLC1A2, OLAH , and RETN. Method according to claim 18, characterized in that step (a) comprises measuring the expression of target genes SIGLEC1, ISG15 and SLC1A2, and of at least three other target genes chosen from HERC6, IL1R2, OLAH, FAM20A, MMP8 and RETN. Method according to claim 18, characterized in that step (a) comprises measuring the expression of a combination of six target genes chosen from the following combinations:
- SIGLEC1_ISG15_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_HERC6_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_ISG15_HERC6_IL1R2_FAM20A_MMP8 ;
- SIGLEC1_SLC1A2_IL1R2_FAM20A_OLAH_MMP8 ;
- SIGLEC1_HERC6_IL1R2_FAM20A_RETN_MMP8 ;
- SIGLEC1_ISG15_IL1R2_FAM20A_RETN_MMP8 ; And
- SIGLEC1_IL1R2_FAM20A_OLAH_RETN_MMP8 Method according to one of claims 1 to 22, characterized in that 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 and in what is concluded to be an infection of a viral nature when the results of comparison of expression of the target genes highlight at least two variations chosen from the following variations:
- overexpression of SIGLEC1,
- overexpression of ISG15,
- overexpression of HERC6,
- an underexpression of SLC1A2,
- an underexpression of IL1R2,
- a subexpression of FAM20A,
- a subexpression of OLAH,
- a subexpression of RETN, and
- an underexpression of MMP8. Method according to one of claims 1 to 22, characterized in that the reference expression value of said target genes corresponds to the respective expression of said target genes in a biological reference sample obtained in a subject having a viral infection and in what is concluded is an infection of a bacterial nature when the results of comparison of expression of the target genes highlight at least two variations of expression chosen from the following variations:
- a subexpression of SIGLEC1,
- a subexpression of ISG15,
- a subexpression of HERC6,
- overexpression of SLC1A2,
- overexpression of IL1R2,
- overexpression of FAM20A,
- an overexpression of OLAH,
- overexpression of RETN, and
- overexpression of MMP8. Method according to one of claims 1 to 24, characterized in that it further comprises a step (a') of measuring the expression of at least one additional target gene chosen from RSAD2, IFI27, OAS1, IFIT1, IFI44L, 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, said reference values corresponding either to the respective expression of said additional target genes in a biological reference sample obtained in a subject having a viral infection, or the respective expression of said additional target genes in a biological reference sample obtained in a subject having a bacterial infection.
. Method according to one of claims 1 to 25, characterized in that the measurement of the expression variation is carried out by amplification via an RT-PCR, preferably a quantitative RT-PCR, or a nested PCR. Method according to one of claims 1 to 26, characterized in that the expression is normalized relative to the expression of one or more housekeeping genes, preferably chosen from DECR1, HPRT1, PPIB, GAPDH, and ACTB. Method according to one of claims 1 to 27, characterized in that the biological sample comes from a child, preferably a child under 4 years old, and more preferably a child under 2 years old. Method according to one of claims 1 to 28, characterized in that the biological sample is a blood sample, preferably a whole blood sample. Kit for in vitro or ex vivo measurement in a biological sample of gene expression at the mRNA level, said kit comprising means for determining the variation in the expression level of at least two genes chosen from SIGLEC1, ISG15, HERC6 , SLC1A2, IL1R2, TIMP4, FAM20A, OLAH, RETN and MMP8, said means being primers or probes. Use of the kit according to claim 30 to determine the viral or bacterial nature of an infection from a biological sample of a subject.