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

描述(申请人提供)：西尼罗河病毒(WNV)是目前所有脑炎黄病毒中传播最广泛的，使其成为全球范围内的一种重要的新兴疾病。感染西尼罗河病毒会在大约1%的人中导致严重的神经系统疾病。关于导致西尼罗河病毒戏剧性传播到新的地理和宿主范围及其神经毒力表型的遗传决定因素，人们知之甚少。将通过在西尼罗河病毒感染性克隆中插入单点突变，并评估在鸟类、蚊子和小鼠中产生的表型，来研究西尼罗河病毒适应、适应和神经毒力的遗传决定因素。具体地说，我将(1)评估不同家系1和2西尼罗河病毒骨架中NS3-249位点的多态对调节禽类宿主能力的表型效应，(2)在小鼠模型中评估不同家系1和2骨架中NS3-249突变对神经侵袭和神经毒力的影响，以及(3)表征含有NS3-249突变的西尼罗河病毒1系和2系病毒在地方性和流行性蚊虫载体中的适合性和传播潜力。

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.