Sex differences in hepatitis A virus infection in mice

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.