title: Neuropathogenesis of Japanese encephalitis in a primate model.
abstract: BACKGROUND
  Japanese encephalitis (JE) is a major cause of mortality and morbidity for which there is no treatment. In addition to direct viral cytopathology, the inflammatory response is postulated to contribute to the pathogenesis. Our goal was to determine the contribution of bystander effects and inflammatory mediators to neuronal cell death.
  
  
  RESULTS
  Material from a macaque model was used to characterize the inflammatory response and cytopathic effects of JE virus (JEV). Intranasal JEV infection induced a non-suppurative encephalitis, dominated by perivascular, infiltrates of mostly T cells, alongside endothelial cell activation, vascular damage and blood brain barrier (BBB) leakage; in the adjacent parenchyma there was macrophage infiltration, astrocyte and microglia activation. JEV antigen was mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death occurred in both infected and non-infected neurons. Interferon-α, which is a microglial activator, was also expressed by both. Tumour Necrosis Factor-α, inducible nitric oxide synthase and nitrotyrosine were expressed by microglial cells, astrocytes and macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons.
  
  
  CONCLUSIONS
  The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines that initiate microglial activation and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. It appears that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of JE.
authors.affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand; Brain Infections Group, Institute of Infection and Global Health, University of Liverpool, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, and Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Khin Saw Aye
authors.initials: KS
authors.lastname: Myint
authors.affiliation: Veterinary Pathology, School of Veterinary Science, and Department of Infection Biology, Institute of Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Anja
authors.initials: A
authors.lastname: Kipar
authors.affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jarman
authors.affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Gibbons
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signal Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Guey Chuen
authors.initials: GC
authors.lastname: Perng
authors.affiliation: Infection Immunology, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Flanagan
authors.affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Duangrat
authors.initials: D
authors.lastname: Mongkolsirichaikul
authors.affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Van Gessel
authors.affiliation: Brain Infections Group, Institute of Infection and Global Health, University of Liverpool, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, and Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004672:Encephalitis, Japanese / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008253:Macaca mulatta; D020782:Matrix Metalloproteinases / Q000032:analysis; D009474:Neurons / Q000201:enzymology / Q000821:virology; D009569:Nitric Oxide / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D020782:Matrix Metalloproteinases
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