Mechanisms of Enhanced Arbovirus Infection by Mosquito Saliva

蚊子唾液增强虫媒病毒感染的机制

• 批准号: 8502089
• 负责人: KRISTEN A BERNARD
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502089
• 关键词: Aedes; Affect; Agriculture; Anopheles Genus; Anopheles gambiae; Antiviral Response; Arbovirus Infections; Arboviruses; Area; Arthropod Vectors; Arthropods; Biochemical; Bioinformatics; Biological Assay; Biology; Birds; Cell Count; Cell Culture Techniques; Cells; Chikungunya virus; Culex (Genus); Culicidae; Data; Dengue; Development; Disease; Distant; Environment; Equine Encephalomyelitis; Evolution; Female; Flavivirus; Gene Expression; Gene Expression Profile; Gene Silencing; Goals; Human; Immune response; Infection; Japanese Encephalitis; Knockout Mice; Mammals; Modeling; Molecular Profiling; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Peripheral; Production; Protein Family; Proteins; Public Health; Qualifying; RNA Interference; Research; Reverse Transcriptase Polymerase Chain Reaction; Rift Valley Fever; Saliva; Salivary; Salivary Proteins; Site; Solid; Study models; System; Systems Biology; Testing; Tick-Borne Encephalitis; Time; Tissues; Transcript; United States National Institutes of Health; Vaccines; Viral; Viral Pathogenesis; Viremia; Virion; Virus; Virus Diseases; West Nile virus; base; burden of illness; enzootic; experience; insight; male; member; mouse model; novel; novel vaccines; pathogen; public health relevance; tool; transmission process; vector; virus host interaction; virus pathogenesis

DESCRIPTION (provided by applicant): Arthropod-borne viruses (arbovirus) are responsible for a significant disease burden worldwide. Here, we will investigate the mosquito-virus-host interaction - an important area of research for all mosquito- borne viruses. Mosquito saliva potentiates viral replication for several different arboviruses, depending on the mosquito species, virus and experimental system; however, the mechanism(s) of enhanced viral replication is not well understood. Investigating these mechanism(s) and identifying the responsible salivary factors are the objectives of this proposal. Our model for these studies will be West Nile virus (WNV), one of its enzootic vectors, Culex tarsalis, and mice as the vertebrate host. Our previous studies showed that mosquito saliva enhances early viral replication in this model. We will build on these studies by pursuing three related aims: 1) Determine how mosquito saliva affects viral production. Since greater viral production is due to either greater numbers of cells infected and/or greater yield per cell, we will explore both possibilities in thes studies. 2) Use a systems biology approach to examine the host response to WNV in the presence of mosquito saliva. Since the enhanced viral replication occurs early after infection, we hypothesize that the innate immune response is inhibited by mosquito saliva. We will use microarray studies to examine differences in expression profiles in target tissues during WNV infection with and without mosquito saliva. 3) Identify the mosquito salivary component(s) responsible for enhancement of WNV infection. Our preliminary studies have narrowed the possible candidates to two protein families found in Culex tarsalis and Aedes aegypti, but not in Anopheles gambiae. We will determine which of these candidates is responsible for viral enhancement and subsequently test it as a possible vaccine. Upon the completion of these aims, we will have made significant contributions to understanding arbovirus pathogenesis in the context of mosquito transmission and laid the groundwork for the development of novel targets to reduce viral transmission.

描述（由申请人提供）：节肢动物传播的病毒（虫媒病毒）在全世界范围内造成了重大的疾病负担。在这里，我们将研究蚊子-病毒-宿主相互作用——这是所有蚊媒病毒研究的重要领域。蚊子唾液可增强几种不同虫媒病毒的病毒复制，具体取决于蚊子种类、病毒和实验系统；然而，增强病毒复制的机制尚不清楚。研究这些机制并确定负责的唾液因素是本提案的目标。我们的这些研究模型将是西尼罗河病毒（WNV）、其地方性传播媒介之一——跗库蚊，以及作为脊椎动物宿主的小鼠。我们之前的研究表明，蚊子唾液可以增强该模型中的早期病毒复制。我们将在这些研究的基础上追求三个相关目标：1）确定蚊子唾液如何影响病毒的产生。由于更大的病毒产量是由于感染的细胞数量更多和/或每个细胞的产量更高，因此我们将在这些研究中探索这两种可能性。 2) 使用系统生物学方法来检查宿主在蚊子唾液存在的情况下对西尼罗河病毒的反应。由于病毒复制增强发生在感染后早期，我们假设先天免疫反应被蚊子唾液抑制。我们将使用微阵列研究来检查在有或没有蚊子唾液的西尼罗河病毒感染期间目标组织中表达谱的差异。 3) 确定导致西尼罗河病毒感染增强的蚊子唾液成分。我们的初步研究已将可能的候选者缩小到在跗库蚊和埃及伊蚊中发现的两个蛋白质家族，但在冈比亚按蚊中却没有。我们将确定这些候选药物中哪一个负责病毒增强，并随后将其作为可能的疫苗进行测试。完成这些目标后，我们将为了解蚊子传播背景下虫媒病毒的发病机制做出重大贡献，并为开发减少病毒传播的新靶点奠定基础。