A deep understanding of the molecular underpinnings underlying severe viral disease outcome in humans is critical for the development of drugs and therapeutics. Controlled human infection studies, in which volunteers are intentionally infected with a pathogen, can advance our understanding of disease pathogenesis as the incubation time, time-course of disease progression, symptomatic rates and immune responses can be closely monitored. In this manuscript published by Yongsheng H et al., PLOS Genetics, 2011, the authors investigated how the transcripts are differentially modulated in the symptomatic and asymptomatic subjects after challenge with the live influenza (H3N2/Wisconsin) strain
17 healthy adults were inoculated with live influenza (H3N2/Wisconsin) strain at 3 different doses (1∶10, 1∶100, 1∶1000, 1∶10000). 9 subjects were symptomatic whereas 8 were asymptomatic. Changes in host peripheral blood gene expression measured at -12, 0, 12, 21, 29, 36, 45, 53, 60, 69, 77, 84, 93, 101 and 108 hrs.
Increasing doses of virus does not correlate with increased symptomatic outcome. This finding is congruent with our previous findings showing vaccine viremia does not influence symptomatic rates (Chan et al., JCI insight, 2017). In contrast, gene signature patterns were strongly associated with disease severity.
Using EDGE with false discovery rate (FDR) significance level (q-value)<0.01, 5,076 genes were temporally changed, comparing between symptomatic and asymptomatic phenotypes. Self-organizing maps (SOM) identified eight distinct classes with differential expression dynamics (See figure above).
Cluster 3 reveal genes that are uniquely increased in symptomatic subjects. These include PRR genes such as Toll-like receptor 7 (TLR7), the RNA helicases (RIG-I), and interferon induced with helicase C domain 1 (IFIH1). In addition, 11 genes from the TLR signaling pathway, including MyD88, TRAF6, and STAT1. NOD1, RIPK2, NOD2, NLPR3, and CASP5 and CASP1 and IL1b were increased in symptomatic subjects but not in the asymptomatic subjects.
Cluster 6 genes identified genes that are uniquely increased in the asymptomatic subjects. Enriched pathways were enriched are related to cellular response to oxidative stress. These include superoxide dismutase (SOD1) and serine/threonine kinase 25 (STK25 or SOK1), which have been linked to anti-oxidant/stress response and reduced concentration of ROS. This cluster also contain genes related to ribosomal synthesis, suggesting that protein biosynthesis could be protective against severe disease.
Both raw and normalized gene expression data are available at GEO (GSE30550).