Abstract
West Nile virus (WNV) is an important cause of viral encephalitis in birds and animals, including humans. Amino acid 159 of the envelope (E) protein is reportedly implicated in the different levels of neurovirulence in mice infected with WNV NY99 or Eg101. We investigated the role of amino acid 159 of the E protein in the pathogenesis of WNV infection. We produced recombinant WNV with the structural proteins of the NY99 or Eg101 strain (NY-WT or EgCME-WT) and mutant viruses with substitutions of amino acid 159 of the E protein (NY-E-V159I or EgCME-E-I159V). The NY-WT and NY-E-V159I or EgCME-WT and EgCME-E-I159V titers in culture supernatant were similar. The mortality rate and viral titer in the brains of mice inoculated intraperitoneally with NY-WT or NY-E-V159I were also similar. In contrast, the mortality rate and viral titer in the brains of mice inoculated intracranially with EgCME-E-I159V were significantly higher than those of mice inoculated with EgCME-WT. The numbers of CD3-positive and CD8-positive T cells were greater in brains inoculated with EgCME-E-I159V than in those inoculated with EgCME-WT. Therefore, amino acid 159 of the E protein modulates the pathogenicity of WNV by affecting viral replication and T-cell infiltration in the brain.
Highlights
West Nile virus (WNV) is a positive-sense RNA flavivirus classified phylogenetically into five distinct genetic lineages[1,2,3]
To investigate the role of amino acid 159 of the E protein in pathogenesis, viral particles containing the NY99-type (Val)-to-Ile and Ile-to-Val mutations were introduced into NY-WT and EgCME-WT, respectively (NY-E-V159I and EgCME-E-I159V; Fig. 1A)
To assess the role of amino acid 159 of the E protein in the pathogenesis, we examined the infiltration of T cells in brains infected with recombinant WNV
Summary
West Nile virus (WNV) is a positive-sense RNA flavivirus classified phylogenetically into five distinct genetic lineages[1,2,3]. The E protein is responsible for entry of WNV into cells and is an important target of neutralising antibodies[7]. Domain I, in the center of the E protein, has a glycosylated amino acid at position 154, which is important for WNV infection of vertebrates[9]. Domain III mediates the attachment of WNV to host cells and is targeted by a number of neutralising monoclonal antibodies[8]. Comparison of the NY99 and Eg101 strains suggested roles for amino acids 156 and 159 of the E protein as determinants of neuroinvasion[12]. We examined the role of amino acid 159 of the E protein in the pathogenesis of WNV in a mouse model by creating mutant WNV strains
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