{"doi":"10.1371/journal.ppat.1009960","title":"IRF3-mediated pathogenicity in a murine model of human hepatitis A","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.","journal":"PLoS Pathogens","year":2021,"id":178831,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":520808,"name":"You Li","orcid":"0000-0001-5458-6009","position":1,"is_corresponding":false},{"id":603293,"name":"Ichiro Misumi","orcid":"0000-0003-3892-7605","position":2,"is_corresponding":false},{"id":612043,"name":"Olga González‐López","orcid":"0000-0002-7685-6302","position":3,"is_corresponding":false},{"id":521548,"name":"Lucinda Hensley","orcid":null,"position":4,"is_corresponding":false},{"id":332071,"name":"John M. Cullen","orcid":"0000-0001-5333-9284","position":5,"is_corresponding":false},{"id":415264,"name":"David R. McGivern","orcid":"0000-0003-3497-5087","position":6,"is_corresponding":false},{"id":151019,"name":"Mami Matsuda","orcid":null,"position":7,"is_corresponding":false},{"id":392333,"name":"Ryosuke Suzuki","orcid":"0000-0003-0296-8843","position":8,"is_corresponding":false},{"id":240328,"name":"Ganes C. Sen","orcid":"0000-0002-9692-0631","position":9,"is_corresponding":false},{"id":609998,"name":"Asuka Hirai-Yuki","orcid":"0000-0002-1218-8333","position":10,"is_corresponding":false},{"id":275085,"name":"Jason K. Whitmire","orcid":"0000-0003-2578-6073","position":11,"is_corresponding":false},{"id":415265,"name":"Stanley M. Lemon","orcid":"0000-0003-1450-806X","position":12,"is_corresponding":false},{"id":292339,"name":"Lu Sun","orcid":"0000-0002-6592-1156","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-18T23:47:40.592580Z","pmid":"34591933","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}