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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\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    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\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice lacking hepatocellular expression of estrogen receptor were phenotypically similar to those expressing\n                    <jats:italic>Esr1<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014660","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:38:42Z","timestamp":1791308322000},"page":"e1014660","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex differences in hepatitis A virus infection in mice"],"prefix":"10.1371","volume":"22","author":[{"given":"Ichiro","family":"Misumi","sequence":"first","affiliation":[{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Genetics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itoe","family":"Shiota","sequence":"additional","affiliation":[{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Genetics"]},{"name":"Foundation for Biomedical Research and Innovation at Kobe","place":["Kobe, Japan"],"department":["Department of Infectious Disease Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Shiota","sequence":"additional","affiliation":[{"name":"Foundation for Biomedical Research and Innovation at Kobe","place":["Kobe, Japan"],"department":["Department of Infectious Disease Research"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Lineberger Comprehensive Cancer Center"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Genetics"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Cullen","sequence":"additional","affiliation":[{"name":"North Carolina State University","place":["Raleigh, North Carolina, United States of America"],"department":["College of Veterinary Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley M.","family":"Lemon","sequence":"additional","affiliation":[{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Lineberger Comprehensive Cancer Center"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Medicine"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Microbiology & Immunology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-6073","authenticated-orcid":true,"given":"Jason K.","family":"Whitmire","sequence":"additional","affiliation":[{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Genetics"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Lineberger Comprehensive Cancer Center"]},{"name":"The University of North Carolina at Chapel Hill","place":["Chapel Hill, North Carolina, United States of America"],"department":["Department of Microbiology & Immunology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"ppat.1014660.ref001","volume-title":"Viral Hepatitis Surveillance Report - United States","author":"CDC","year":"2023"},{"issue":"6","key":"ppat.1014660.ref002","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/hep.21439","article-title":"Fulminant hepatitis A virus infection in the United States: Incidence, prognosis, and outcomes","volume":"44","author":"RM Taylor","year":"2006","journal-title":"Hepatology"},{"key":"ppat.1014660.ref003","article-title":"Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention","author":"SM Lemon","year":"2017","journal-title":"J Hepatol"},{"issue":"3","key":"ppat.1014660.ref004","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/infdis\/jiaa636","article-title":"Hepatitis A person-to-person outbreaks: Epidemiology, 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