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Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus na\u00efve <jats:italic>Mavs<\/jats:italic><jats:sup>-\/-<\/jats:sup> and <jats:italic>Ifnar1<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in <jats:italic>Mavs<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in <jats:italic>Ifnar1<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with <jats:italic>Ifnar1<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected <jats:italic>Irf3<\/jats:italic><jats:sup><jats:italic>S1\/S1<\/jats:italic><\/jats:sup><jats:italic>Ifnar1<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in <jats:italic>Irf3<\/jats:italic><jats:sup><jats:italic>S1\/S1<\/jats:italic><\/jats:sup><jats:italic>Ifnar1<\/jats:italic><jats:sup>-\/-<\/jats:sup> and <jats:italic>Ifnar1<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2\u2019-5\u2019 oligoadenylate synthetase families. <jats:italic>Ifnl3<\/jats:italic> and <jats:italic>Ifnl2<\/jats:italic> transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009960","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T19:42:00Z","timestamp":1633030920000},"page":"e1009960","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["IRF3-mediated pathogenicity in a murine model of human hepatitis 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