Phenotypic Characterization of Mutations Made to the Envelope Protein of West Nile Virus



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West Nile virus (WNV) is a mosquito-borne flavivirus that can cause severe neuroinvasive disease resulting in death or long term neurological sequela. The envelope (E) protein of flaviviruses has three domains and is the major component of the virion surface, with the EIII being the putative receptor binding domain. Previous studies showed that Gly to Ala mutation of EIII residue 331 (G331A) yielded a virus that had altered antigenicity, slightly restricted growth in Vero cells, and a highly attenuated phenotype in mouse models of neuroinvasive disease. This study aimed to characterize the impact that G331A mutation made on phenotypes that have been associated with attenuation of neurotropic flaviviruses. The central hypothesis for these studies was that attenuation induced by the G331A mutation is due to alteration of WNV EIII structure and/or stability and alters WNV interactions with host cells in vitro and in vivo. Experimental results demonstrated that G331A mutation induces significantly attenuated neurovirulent and neuroinvasive phenotypes, and that the mutation impacted multiple phenotypes associated with attenuation of neurotropic flaviviruses. Furthermore, multiple experimental conditions were shown to select for revertant or adaptive mutations. Collectively, the results from this study showed that G331A mutation induces a multifactorial attenuation of WNV and that an additional revertant mutation (H395Y) restores many, but not all, of the impacted phenotypes.



Biology, Virology