Characteristics of Japanese encephalitis virus infection in NCG-hSTAT2+/+ mice: a novel model for studying neurological symptoms and immune response

Japanese encephalitis virus (JEV), a leading cause of viral encephalitis in Asia and the Western Pacific, is regulated by type I interferon (IFN) signaling pathway, in which STAT2 is critical. However, the exact role of STAT2 in JEV-mediated IFN evasion remains unclear. Existing murine models of JEV infection predominantly employ high viral titers to induce encephalitis and primarily use immunocompetent or IFN receptor-deficient mice, limiting their use to study the IFN evasion mechanisms of JEV. To address this, we developed a humanized STAT2 mouse model (NCG-hSTAT2+/+) and infected it with 10³ PFU of JEV-p3. These mice exhibited severe encephalitis resembling clinical human infections, characterized by elevated viral load, and increased proinflammatory cytokines. Especially, they presented typical neurological symptoms, such as activated astrocytes and distinct neuropathological changes. This suggests that NCG-hSTAT2+/+ mice exhibit higher susceptibility to JEV and more-severe neurological symptoms, which is consistent with the clinical manifestations observed in human patients. This mouse model significantly advances the study of JEV pathogenesis, the therapeutic evaluation of this infection and the role human STAT2 has in neuroinvasion and immune evasion.