IRF3-mediated pathogenicity in a murine model of human hepatitis A

Hepatitis A virus (HAV), an hepatotropic picornavirus, is a common cause of acute hepatitis in human populations. Although responsible for considerable morbidity and mortality, the mechanisms underlying HAV-mediated liver injury are poorly understood. Ifnar1-/- mice are susceptible to HAV and when infected recapitulate cardinal features of hepatitis A in humans, including serum ALT elevation, hepatocellular apoptosis, and intrahepatic inflammatory cell infiltrates. In contrast, Mavs-/- mice, while equally permissive for infection, experience no liver injury. Previous studies indicate that HAV pathogenesis in Ifnar1-/- mice is dependent upon MAVS-IRF3 signaling, but leave unresolved the role of IRF3-mediated transcription versus non-transcriptional pro-apoptotic activity of activated IRF3 in HAV-induced liver disease. Here, we compared the intrahepatic transcriptomes of HAV-infected naïve Mavs-/- and Ifnar1-/- mice using high throughput RNA sequencing, and characterized IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Liver mRNA profiles of Ifnar1-/- ,Mavs-/- and Irf3S1/S1Ifnar1-/- mice 7 days or 14 days after HAV infection