title: Glial activation involvement in neuronal death by Japanese encephalitis virus infection.
abstract: Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-alpha, IL-1beta, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-alpha/IL-1beta expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-alpha and IL-1beta, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan, ROC. cjchen@vghtc.gov.tw
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Shue-Ling
authors.initials: SL
authors.lastname: Raung
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Lai
authors.forename: Shih-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004664:Encephalitis Virus, Japanese / Q000472:pathogenicity*; D005911:Gliosis; D018836:Inflammation Mediators / Q000502:physiology; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D004247:DNA