{ "abstract": "Epidemiological studies show that more men are hospitalized for severe hepatitis A than women. However, the extent to which social and behavioral differences versus intrinsic biological mechanisms account for this disparity in disease incidence remains unclear. To better define how sex influences infection outcome, we challenged male and female Ifnar1-/- mice with HAV and quantified virus replication and liver injury. Male mice replicated and shed more virus than female mice, and demonstrated both accelerated and more severe liver injury, as evidenced by increased serum alanine aminotransferase (ALT) activity, greater immune cell infiltration in the liver, and higher intrahepatic expression of chemokines and interferon-stimulated genes. Sex differences were apparent in young and older adult mice, indicating that age did not significantly influence these effects. Ovariectomized female mice had higher intrahepatic viral loads, greater serum ALT elevation, and more severe pathology, compared to surgical controls. Conversely, ovariectomized mice given estradiol implants showed reduced viral loads and ALT activity, indicating that estrogen exerts a protective effect. Female Ifnar1-/- mice lacking hepatocellular expression of estrogen receptor were phenotypically similar to those expressing Esr1, indicating that direct ESR1 signaling in hepatocytes is not essential for protection against pathogenesis. Collectively, these findings indicate that sex influences the pathogenesis and outcome of HAV infection and that female sex hormones protect against severe liver injury. Author summary: The virological and pathological consequences of virus infections can be affected by the sex of the host. Men are hospitalized more frequently for acute hepatitis A than women, but whether this is due directly to sex versus gender-related epidemiological factors is not known. Herein, we compared HAV infections in male and female Ifnar1-/- mice. Male mice replicated more virus and experienced greater HAV-related liver injury than females. Analyses of infection in ovariectomized mice indicated that female sex hormones limit both virus replication and pathogenesis. Estradiol-mediated signaling contributes to this protection, although signaling via ESR1 into hepatocytes is not essential. Collectively, these findings suggest that the greater incidence of hospitalization for acute hepatitis A in men may be due in part to sex-related differences in biology. (125 words)", "abstract_shown": true, "affiliations": [ "Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America", "Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan", "Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America", "Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America", "College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America", "Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America", "Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0 ], "name": "Ichiro Misumi" }, { "affs": [ 1 ], "name": "Itoe Shiota" }, { "affs": [ 2 ], "name": "Tomoyuki Shiota" }, { "affs": [ 3 ], "name": "Jingyu Zhao" }, { "affs": [ 4 ], "name": "John M. Cullen" }, { "affs": [ 5 ], "name": "Stanley M. Lemon" }, { "affs": [ 6 ], "name": "Jason K. Whitmire" } ], "bibtex": "https://research.draconitic.com/paper/970c50acxtmtv.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014660", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014660", "id": "970c50acxtmtv", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014660", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2721|Hepatitis Viruses Studies and Epidemiology" ], [ "plos", "/Biology and life sciences/Anatomy/Liver/Hepatocytes" ], [ "plos", "/Biology and life sciences/Biochemistry/Hormones/Sex hormones" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Cell death/Apoptosis" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Hepatocytes" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis A virus" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Hepatitis viruses/Hepatitis A virus" ], [ "plos", "/Medicine and health sciences/Anatomy/Liver/Hepatocytes" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis A virus" ], [ "plos", "/Medicine and health sciences/Surgical and invasive medical procedures/Reproductive system procedures/Ovariectomy" ], [ "plos", "/Medicine and health sciences/Surgical and invasive medical procedures/Surgical excision/Ovariectomy" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Mouse models" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Mouse models" ], [ "plos", "/Research and analysis methods/Model organisms/Mouse models" ] ], "openalex": "W7220738987", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014660&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-06", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/970c50acxtmtv.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014660", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014660" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Sex differences in hepatitis A virus infection in mice", "title_text": "Sex differences in hepatitis A virus infection in mice", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:30Z", "url": "https://research.draconitic.com/paper/970c50acxtmtv", "venue": "PLOS Pathogens", "versions": [] }