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.