The PGC-1α Axis Links Estrogen Receptor-α Signaling to Japanese Encephalitis Virus Replication in Neuronal Cells

Acute encephalitis due to the viral causative agents, such as Japanese Encephalitis Virus (JEV), remains a leading cause of viral encephalitis in Asia, contributing to high mortality and long-term neurological sequelae. The host factors that modulate JEV replication are not well understood. In this study, we investigated the modulation of JEV infection by estrogen in vitro and in vivo . The results demonstrated that estrogen enhances JEV replication in neuronal cells via estrogen receptor alpha (ERα) by modulating peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Since JEV pathogenesis increases cellular production demands, it results in dysregulation of cellular homeostasis, whereas estrogen treatment helps keep cellular health in check. Also, the mouse model exhibited an increased viral burden with protective antibody titers in response to estrogen. Conclusively, this work highlights the mechanistic link of estrogen-driven mechanisms and identifies the ERα-PGC-1α-axis as a potential target for sex-specific therapeutic interventions.