Mosquito-Virus-Host Interactions and WNV Pathogenesis

描述（由申请人提供）：节肢动物传播的病毒（虫媒病毒）存在于其节肢动物载体和脊椎动物宿主之间的复杂循环中。西尼罗河病毒（WNV）是一种引起重大人类和兽医疾病的虫媒病毒，通过鸟类和库蚊之间的循环在自然界中得以维持。蚊子-病毒-脊椎动物宿主的动态相互作用不仅关系到地方性传播的效率，而且关系到疾病的发病机制。目前，蚊虫传播对脊椎动物感染西尼罗河病毒的影响尚不明确。本研究计划的目的是进一步了解西尼罗河病毒与其脊椎动物和无脊椎动物宿主的相互作用，以制定新的控制和治疗策略。初步数据显示，经蚊子感染西尼罗河病毒的鸡的早期病毒血症比针接种高100倍，据此，中心假设是蚊虫传播增强了西尼罗河病毒在脊椎动物宿主中的早期感染。验证这一假设的研究将采用以下方法：1)将比较西尼罗河病毒在鸡和小鼠中的自然蚊子传播和针接种的初级和次级复制位点的病毒复制；2)将测试蚊虫传播西尼罗河病毒的不同方面对鸡易得病毒血症的影响，包括病毒剂量、唾液、蚊虫探测和蚊源病毒；3)确定早期病毒血症的机制，特别是对宿主I型干扰素反应的影响将在体内和体外进行研究。本研究的完成将进一步阐明西尼罗河病毒与扩增宿主（鸟类）和附带宿主（小鼠）蚊子的相互作用，并将明确蚊子唾液在西尼罗河病毒传播和疾病中的关键作用。本应用中提出的研究具有重要意义，因为了解这种复杂的相互作用对于开发西尼罗河病毒的创新治疗和控制策略至关重要。

Description (provided by applicant): Arthropod-borne viruses (arboviruses) exist in a complex cycle between their arthropod vector and vertebrate host. West Nile virus (WNV), an arbovirus that causes significant human and veterinary disease, is maintained in nature by cycling between birds and Culex spp. mosquitoes. The dynamic mosquito-virus vertebrate host interaction is involved not only in the efficiency of enzootic transmission, but also in the pathogenesis of disease. Currently, the impact of mosquito transmission on WNV infection in the vertebrate is poorly defined. The objective of this research proposal is to further our understanding of the interaction of WNV with its vertebrate and invertebrate hosts in order to develop novel control and treatment strategies. Based on preliminary data that early viremia is 100-fold higher in chickens infected with WNV by mosquitoes compared to needle inoculation, the central hypothesis is that mosquito transmission enhances the earliest steps of WNV infection in its vertebrate host. Studies to test this hypothesis will use the following approaches: 1) viral replication in primary and secondary sites of replication will be compared for natural mosquito transmission and needle inoculation of WNV in chickens and mice; 2) different aspects of mosquito transmission of WNV will be tested for their effect on eady viremia in chickens, including viral dose, saliva, mosquito probing and mosquito-derived virus; 3) the mechanism responsible for the early viremia will be identified, and in particular the effect on the host's Type I interferon response will be examined in vivo and in vitro. Completion of this study will further elucidate the interaction of WNV and the mosquito with amplifying (bird) and incidental (mouse) hosts and will define the critical role that mosquito saliva plays in WNV transmission and disease. The research proposed in this application is significant because understanding this complex interaction is essential to developing innovative treatment and control strategies for WNV.