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A molecular determinant of West Nile virus secretion and morphology as a target for viral attenuation

Abstract : West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to re-emerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with Flavivirus-induced pathogenesis. Here we identify a key amino acid residue at position 36 of the M protein whose mutation impacts WNV secretion and promotes viral attenuation. We also identified a compensatory site at position M-43 whose mutation stabilizes M-36 substitution both in vitro and in vivo. Moreover, we find that introduction of the two mutations together confers a full attenuation phenotype and protection against wild-type WNV lethal challenge, eliciting potent neutralizing antibody production in mice. Our study thus establishes the M protein as a new viral target for rational design of attenuated WNV strains. IMPORTANCE West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted Flavivirus causing fatal neurological diseases in humans. However, no human vaccine has been yet approved. One of the most effective live-attenuated vaccines was empirically obtained by serial passaging of wild-type yellow fever Flavivirus. However, such an approach is not acceptable nowadays and the development of vaccine rationally designed is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in Flavivirus virulence is a powerful tool to promote viral attenuation. WNV membrane glycoprotein is thought to carry such essential determinants. Here, we identified two residues of this protein whose substitutions are key to the full and stable attenuation of WNV in vivo, most likely through inhibition of secretion and possible alteration of morphology. Applied to other flaviviruses, this approach should help in designing new vaccines against these viruses that are an increasing threat to global human health.
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Submitted on : Tuesday, April 21, 2020 - 11:07:40 AM
Last modification on : Wednesday, September 16, 2020 - 10:20:04 AM

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Justine Basset, Julien Burlaud-Gaillard, Maxence Feher, Philippe Roingeard, Felix Rey, et al.. A molecular determinant of West Nile virus secretion and morphology as a target for viral attenuation. Journal of Virology, American Society for Microbiology, In press, ⟨10.1128/JVI.00086-20⟩. ⟨pasteur-02549098⟩

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