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: 8868017
• 负责人: KRISTEN A BERNARD
• 金额: $ 37.63万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868017
• 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; Health; 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; 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 - 传播病毒（Arbovirus）负责全球重大疾病负担。在这里，我们将研究蚊子 - 病毒 - 宿主相互作用 - 所有蚊子传播病毒的重要研究领域。蚊子唾液增强了几种不同芳族病毒的病毒复制，具体取决于蚊子，病毒和实验系统。但是，增强病毒复制的机制尚不清楚。研究这些机制并确定负责任的唾液因素是该提议的目标。我们的这些研究模型将是西尼罗河病毒（WNV），其Enzootic载体之一，Culex Tarsalis和小鼠是脊椎动物宿主。我们先前的研究表明，蚊子在该模型中增强了早期病毒复制。我们将通过追求三个相关目标来建立这些研究：1）确定蚊子如何影响病毒生产。由于较大的病毒产生是由于每个细胞感染了更多的细胞和/或更高的产量，因此我们将在研究中探索这两种可能性。 2）使用系统生物学方法在存在蚊子存在下检查宿主对WNV的反应。由于增强的病毒复制发生在感染后早期发生，因此我们假设先天免疫反应受到蚊子唾液的抑制。我们将使用微阵列研究检查WNV感染期间有或没有蚊子唾液的WNV感染期间目标组织中表达谱的差异。 3）确定负责增强WNV感染的蚊子唾液成分。我们的初步研究将可能的候选物缩小到在Culex tarsalis和Aedes Aegypti中发现的两个蛋白质家族，但在Anopheles Gambiae中没有。我们将确定哪些候选者负责病毒增强，然后将其作为可能的疫苗进行测试。这些目标完成后，我们将在蚊子传播的背景下为理解Arbovirus发病机理做出了重大贡献，并为开发新靶标而奠定了基础，以减少病毒传播。