Pathogenic Mechanisms of Japanese Encephalitis Virus Infection in Mammals

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus and the leading cause of viral encephalitis in many regions of Asia. Owing to its pronounced neurotropism, JEV infection can result in severe neurological disease with high mortality, while 30–50% of survivors develop permanent neurological sequelae. Although substantial progress has been made over the past few decades, the molecular mechanisms underlying JEV infection, neuroinvasion, and host-mediated pathogenesis remain incompletely understood. In this review, we summarize recent advances in the understanding of JEV pathogenesis from both viral and host perspectives. We discuss the key events during JEV infection in mammalian hosts, including viral attachment and entry, replication and dissemination, viral determinants of virulence, blood–brain barrier penetration, and the mechanisms underlying central and peripheral nervous system injury. We further compare currently available experimental models for JEV research, including mouse models, porcine models, and human brain organoid systems, highlighting their respective applications, advantages, and limitations in investigating JEV pathogenesis. Collectively, this review provides an integrated overview of the molecular and cellular mechanisms governing JEV infection and neuropathogenesis, identifies current knowledge gaps, and discusses future research priorities that may facilitate the development of effective antiviral and neuroprotective strategies against Japanese encephalitis.