Institut Pasteur, Arbovirus Group, Environment and Infectious Risks Unit, Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.
J Virol. 2020 Jun 1;94(12). doi: 10.1128/JVI.00086-20.
West Nile virus (WNV), a member of the genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with -induced pathogenesis. Here, we identified 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 and Moreover, we found 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. West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted 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 However, such an approach is not acceptable nowadays, and the development of a rationally designed vaccine is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in virulence constitute 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 , 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, which are an increasing threat to global human health.
西尼罗河病毒（WNV）是属的一种病毒，也是目前世界上最常见的虫媒病毒之一，可引起人类严重的神经疾病。其重新出现和快速传播的高潜力使其成为真正的全球公共卫生问题。表面膜糖蛋白（M）与诱导的发病机制有关。在这里，我们确定了 M 蛋白第 36 位的一个关键氨基酸残基，其突变会影响 WNV 的分泌并促进病毒衰减。我们还鉴定了 M-43 位置的一个补偿性位点，其突变稳定了 M-36 取代，无论是在体内还是在体外。此外，我们发现引入这两个突变会赋予完全衰减表型，并能防止野生型 WNV 致命性挑战，在小鼠中引发有效的中和抗体产生。因此，我们的研究确立了 M 蛋白作为合理设计减毒 WNV 株的新病毒靶标。西尼罗河病毒（WNV）是一种在全世界（重新）出现的蚊媒传播病毒，可导致人类致命的神经疾病。然而，目前还没有批准用于人类的疫苗。最有效的减毒活疫苗之一是通过对野生型黄热病的连续传代经验性获得的。然而，如今这种方法是不可接受的，因此有必要开发一种合理设计的疫苗。生成分子传染性克隆并突变已知与毒力有关的特定残基，这是促进病毒衰减的有力工具。WNV 膜糖蛋白被认为携带这种必要的决定因素。在这里，我们确定了该蛋白的两个残基，其取代是 WNV 完全和稳定衰减的关键，这很可能是通过抑制分泌和可能改变形态来实现的。将这种方法应用于其他黄病毒，应该有助于设计针对这些病毒的新疫苗，这些病毒对全球人类健康构成日益严重的威胁。
