ArticlePLoS pathogens2021
IRF3-mediated pathogenicity in a murine model of human hepatitis A.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Sex differences in hepatitis A virus infection in mice.PLoS pathogens · 2026Article
- Advances and perspectives in animal models of human hepatitis A virus.Animal models and experimental medicine · 2026Review
- Host species-specific mutations in the thumb domain of the 3Dpol polymerase are required for efficient replication of human hepatitis A virus in mice.PLoS pathogens · 2026Article
- An engineered human hepatitis A virus capable of rapid proliferationJHEP reports : innovation in hepatology · 2025Article
- Natural killer cells and IFN-γ protect against liver injury during HAV infection in mice.Journal of virology · 2025Article
- Hepatovirus translation requires PDGFA-associated protein 1, an eIF4E-binding protein regulating endoplasmic reticulum stress responses.Science advances · 2024Article
- Biochemical analysis of the host factor activity of ZCCHC14 in hepatitis A virus replication.Journal of virology · 2024Article
- Hepatitis A virus infection.Nature reviews. Disease primers · 2023Review
- GepLiver: an integrative liver expression atlas spanning developmental stages and liver disease phases.Scientific data · 2023Article
- Viral protease cleavage of MAVS in genetically modified mice with hepatitis A virus infection.Journal of hepatology · 2023Article
- Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A inJournal of virology · 2022Article
- Nonlytic Quasi-Enveloped Hepatovirus Release Is Facilitated by pX Protein Interaction with the E3 Ubiquitin Ligase ITCH.Journal of virology · 2022Article
- The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice.Virologica Sinica · 2022Article
- Pathogenesis of Alcohol-Associated Liver Disease.Journal of clinical and experimental hepatologyReview
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13 authors.
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Abstract
HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. 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 naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- 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 Ifnar1-/- 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 Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- 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 Irf3S1/S1Ifnar1-/- and Ifnar1-/- 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'-5' oligoadenylate synthetase families. Ifnl3 and Ifnl2 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.
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