Molecular Analysis of the Genetic Determinants that Contribute to Virulence in We

描述（由申请方提供）：西尼罗河病毒（WNV）是目前所有脑炎黄病毒中分布最广的一种，使其成为全球范围内重要的新兴疾病。感染西尼罗河病毒会在大约1%的人中产生严重的神经系统疾病。很少有人知道的遗传决定因素，有助于戏剧性传播西尼罗河病毒到新的地理和主机范围和其神经毒力表型。将通过在WNV感染性克隆中插入单点突变并评估鸟类，蚊子和小鼠中产生的表型来研究WNV适应，健身和神经毒力的遗传决定因素。具体而言，我将（1）评估不同谱系1和2 WNV骨架中NS 3 -249位点多态性对禽类宿主能力调节的表型效应，（2）评估小鼠模型中不同谱系1和2骨架中NS 3 -249突变的神经侵袭性和神经毒力效应，和（3）表征含有NS 3 -249突变的WNV谱系1和2病毒在地方病和流行病蚊子载体中的适应性和传播潜力。

DESCRIPTION (provided by applicant): West Nile Virus (WNV) is currently the most widely dispersed of all encephalitic flaviviruses, making it an important emerging disease worldwide. Infection with WNV produces severe neurological disease in approximately 1 percent of individuals. Little is known about the genetic determinants that have contributed to the dramatic dissemination of WNV to new geographic and host ranges and its neurovirulent phenotype. Genetic determinants for WNV adaption, fitness and neurovirulence will be investigated by inserting single point mutations in WNV infectious clones and evaluating the resulting phenotypes in birds, mosquitoes and mice. Specifically, I will (1) assess the phenotypic effects of polymorphisms at the NS3-249 site in different lineage 1 and 2 WNV backbones for modulation of avian host competence, (2) assess the neuroinvasive and neurovirulence effects of the NS3-249 mutation in different lineage 1 and 2 backbones in a mouse model, and (3) characterize the fitness and transmission potential of WNV lineage 1 and 2 viruses containing a NS3-249 mutations in enzootic and epizootic mosquito vectors.