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, STAT2's exact role 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 utility for studying JEV's IFN evasion mechanisms. 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 loads, and increased proinflammatory cytokines. Especially, it presents 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 that observed in clinical patients exhibited. This model significantly advances the study of JEV pathogenesis, therapeutic evaluation, and understanding of human STAT2's role in neuroinvasion and immune evasion.