A Four-Biomarker Blood Signature Discriminates Systemic Inflammation Due to Viral Infection Versus Other Etiologies

D L Sampson,S Bhide,L C Mchugh,T A Seldon,T D Yager,B A Fox,R A Brandon,M Noursadeghi,S Cermelli,R B Brandon,E Sullivan,J J Zimmerman

doi:10.1038/s41598-017-02325-8

Abstract

The innate immune system of humans and other mammals responds to pathogen-associated molecular patterns (PAMPs) that are conserved across broad classes of infectious agents such as bacteria and viruses. We hypothesized that a blood-based transcriptional signature could be discovered indicating a host systemic response to viral infection. Previous work identified host transcriptional signatures to individual viruses including influenza, respiratory syncytial virus and dengue, but the generality of these signatures across all viral infection types has not been established. Based on 44 publicly available datasets and two clinical studies of our own design, we discovered and validated a four-gene expression signature in whole blood, indicative of a general host systemic response to many types of viral infection. The signature’s genes are: Interferon Stimulated Gene 15 (ISG15), Interleukin 16 (IL16), 2′,5′-Oligoadenylate Synthetase Like (OASL), and Adhesion G Protein Coupled Receptor E5 (ADGRE5). In each of 13 validation datasets encompassing human, macaque, chimpanzee, pig, mouse, rat and all seven Baltimore virus classification groups, the signature provides statistically significant (p < 0.05) discrimination between viral and non-viral conditions. The signature may have clinical utility for differentiating host systemic inflammation (SI) due to viral versus bacterial or non-infectious causes.

Highlights

Displaced by immunological and molecular methods such as rapid immunoassays and polymerase chain reaction (PCR)[11, 12], these newer methods suffer from limitations, for example: (i) an inability to detect organisms not represented in an immunoassay or PCR panel; (ii) an inability to discriminate between live and dead organisms in a specimen; and (iii) a tendency to detect low levels of virus that may not be clinically relevant[13]
A comprehensive, stepwise filtering approach was applied to 19 additional GEO datasets comprising a total of 1337 cases and 1106 controls (Table 1), to exclude genes that were differentially expressed in conditions that may present as SI but appear unrelated to viral systemic inflammation
The end result, after the filtering step was applied, was a “pan-viral” signature based on the expression levels of four genes: Interferon Stimulated Gene (ISG15), Interleukin (IL16), 2′,5′-Oligoadenylate Synthetase Like (OASL), and Adhesion G Protein Coupled Receptor E5 (ADGRE5)

Summary

Introduction

Displaced by immunological and molecular methods such as rapid immunoassays and polymerase chain reaction (PCR)[11, 12], these newer methods suffer from limitations, for example: (i) an inability to detect organisms not represented in an immunoassay or PCR panel; (ii) an inability to discriminate between live and dead organisms in a specimen; and (iii) a tendency to detect low levels of virus that may not be clinically relevant[13] Given these limitations, increasing attention is being paid to an alternative approach: that of identifying biomarkers that reflect the differential host response to underlying non-infectious, bacterial, or viral conditions[14,15,16,17,18,19,20,21,22,23]. This viral signature relies on only four biomarkers, and this high degree of parsimony should help to ensure the performance robustness necessary for effective translation to a rapid point-of-care format

Methods

Results

Conclusion