TNF-α Acts as an Immunoregulator in the Mouse Brain by Reducing the Incidence of Severe Disease Following Japanese Encephalitis Virus Infection

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-alpha in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-alpha KO mice was significantly increased compared with that of WT mice, indicating that TNF-alpha plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-alpha KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-alpha KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-alpha KO mice. Our findings therefore provide the first evidence that TNF-alpha has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-alpha in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-alpha will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.