Sex differences in hepatitis A virus infection in mice
7 affiliations
- 1Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- 2Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
- 3Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- 4Division 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
- 5College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America
- 6Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- 7Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
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)
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BibTeX
@article{misumi2026differences,
title = {{Sex differences in hepatitis A virus infection in mice}},
author = {Ichiro Misumi and Itoe Shiota and Tomoyuki Shiota and Jingyu Zhao and John M. Cullen and Stanley M. Lemon and Jason K. Whitmire},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014660},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014660},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex differences in hepatitis A virus infection in mice
AU - Ichiro Misumi
AU - Itoe Shiota
AU - Tomoyuki Shiota
AU - Jingyu Zhao
AU - John M. Cullen
AU - Stanley M. Lemon
AU - Jason K. Whitmire
PY - 2026
DA - 2026/10/06
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014660
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014660
AB - 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)
SN - 1553-7374
ER -