title: Type-I interferon response affects an inoculation dose-independent mortality in mice following Japanese encephalitis virus infection.
abstract: BACKGROUND
  The laboratory mouse model is commonly employed to study the pathogenesis of encephalitic flaviviruses such as Japanese encephalitis virus (JEV). However, it is known that some strains of these viruses do not elicit a typical mortality dose response curve from this organism after peripheral infection and the reason for it has not yet been fully understood. It is suggested that induction of more vigorous Type-I IFN (IFN-I) response might control early virus dissemination following increasing infectious challenge doses of the virus. Thus, the objective of this study was to examine this suggested role of IFN-I in the mortality of mice infected with various doses of JEV.
  
  
  METHODS
  Inbred 129 mice and their IFNAR KO (A129) mice were subcutaneously inoculated with 100, 102, 104 or 106 pfu of JaOArS982 strain of JEV. Mice were weighed daily and observed for clinical signs. Virus titers in the brains and spleens of JEV-infected mice were determined by plaque forming assays. The upregulated mRNA levels of genes related to IFN-I response of mice were examined by real-time PCR.
  
  
  RESULTS
  The mortality rates of 129 mice infected with JaOArS982 did not significantly increase despite the increase in inoculation dose and no significant difference of viral loads was observed between their brains. However, there was clear elevation of the mRNA levels of interferon regulatory factor (IRF)3, IRF7, IRF9, MDA5 and RIG-I at 24 hours post-infection depending on the inoculation dose. In A129 mice, length of survival days and the viral loads of spleen and brain were observed to be inoculation dose-dependent.
  
  
  CONCLUSIONS
  From these results, it is suggested that early IFN-I response elicited by high inoculation doses of JEV provides an anti-viral effect during the early phase of infection. Accordingly, virus replication is counteracted by IFN-I response at each increasing inoculation dose resulting in the interference of impending severe disease course or fatal outcome; hence, this might explain the inoculation dose-independent mortality in mice caused by Japanese encephalitis virus.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Aoki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimada
authors.forename: Dash Sima
authors.initials: DS
authors.lastname: Simantini
authors.forename: Mya Myat Ngwe
authors.initials: MM
authors.lastname: Tun
authors.forename: Corazon C
authors.initials: CC
authors.lastname: Buerano
authors.forename: Kouichi
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hayasaka
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D004195:Disease Models, Animal; D004664:Encephalitis Virus, Japanese / Q000276:immunology*; D004672:Encephalitis, Japanese / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D020869:Gene Expression Profiling; D007370:Interferon Type I / Q000276:immunology*; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000821:virology; D016019:Survival Analysis; D019562:Viral Load; D010948:Viral Plaque Assay
chemical_list: D007370:Interferon Type I