Mosquito-Virus-Host Interactions and WNV Pathogenesis

描述（申请人提供）：节肢动物传播病毒（虫媒病毒）在其节肢动物载体和脊椎动物宿主之间存在复杂的循环。西尼罗河病毒（WNV）是一种引起人类和兽医疾病的虫媒病毒，通过在鸟类和库蚊属之间循环而在自然界中维持。蚊子蚊媒病毒与脊椎动物宿主间的动态相互作用不仅影响了病毒在动物体内的传播效率，而且也影响了疾病的发病机制。目前，蚊子传播对脊椎动物中西尼罗河病毒感染的影响尚不清楚。这项研究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，以开发新的控制和治疗策略。根据初步数据，早期病毒血症是100倍高的鸡感染西尼罗河病毒的蚊子相比，针接种，中心假设是蚊子传播增强了最早的步骤西尼罗河病毒感染的脊椎动物宿主。为了验证这一假说，将采用以下方法：1）比较蚊虫自然传播和针接种的病毒在主要复制位点和次要复制位点的复制情况：2）从病毒剂量、唾液、蚊虫刺入和蚊源病毒等方面，检测蚊虫传播的病毒对鸡早期病毒血症的影响; 3）将鉴定导致早期病毒血症的机制，特别是将在体内和体外检查对宿主的I型干扰素应答的影响。这项研究的完成将进一步阐明西尼罗河病毒和蚊子与扩增（鸟类）和偶然（小鼠）宿主的相互作用，并将确定蚊子唾液在西尼罗河病毒传播和疾病中的关键作用。本申请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.