Mosquito-Virus-Host Interactions and WNV Pathogenesis

节肢动物传播的病毒(虫媒病毒)在其节肢动物媒介和 脊椎动物宿主。西尼罗河病毒(WNV)，一种能引起重大人类和兽医疾病的虫媒病毒， 在自然界中是通过在鸟类和库蚊之间循环而维持的。蚊子。动态的蚊子病毒- 脊椎动物与宿主的相互作用不仅关系到地方性疾病的传播效率，而且还关系到 疾病的发病机制。目前，蚊子传播对脊椎动物感染西尼罗河病毒的影响 定义不明确。这项研究建议的目的是加深我们对 西尼罗河病毒及其脊椎动物和无脊椎动物宿主，以开发新的控制和治疗策略。 根据初步数据，被蚊子感染西尼罗河病毒的鸡的早期病毒血症高出100倍 与针头接种相比，中心假设是蚊子传播增强得最早 西尼罗河病毒在脊椎动物宿主中的感染步骤。检验这一假设的研究将使用以下方法 方法：1)在主站点和辅助站点复制病毒[复制将与自然复制进行比较 西尼罗河病毒在鸡和小鼠体内的蚊虫传播和针接种；2)蚊子的不同方面 将测试西尼罗河病毒的传播对鸡Eady病毒血症的影响，包括病毒剂量，唾液， 蚊虫探测和蚊媒病毒；3)早期病毒血症的机制将是 确定，特别是对宿主的I型干扰素反应的影响将在体内和在 体外培养。这项研究的完成将进一步阐明西尼罗河病毒与蚊子之间的相互作用和扩增 (鸟类)和偶然的(老鼠)宿主，并将确定蚊子唾液在西尼罗河病毒中所起的关键作用 传播和疾病。本申请中提出的研究具有重要意义，因为理解了这一点 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。

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 o[ 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.