Mosquito Immunity to Alphaviruses

描述(申请人提供)：蚊媒疾病的再次出现和全球传播正在降低世界各地人类和野生动物种群的健康，并对世界经济造成越来越大的消耗。特别是，蚊媒病毒正在流行地区重新出现，并迅速传播到全球新的范围(例如。美洲的西尼罗河病毒、中东的裂谷热病毒、非洲的奥尼翁-尼翁病毒)。作为传播的基本过程，这些虫媒病毒必须在蚊子的肠道组织中复制，在蚊子体内传播，并最终感染蚊子的唾液腺。利用表达绿色荧光蛋白的甲型病毒转导系统，我们已经能够表征虫媒病毒在蚊子中的传播途径。我们还利用了目前可用的冈比亚按蚊和埃及伊蚊的基因组数据，并利用这些数据开始描述媒介蚊子传播的障碍。通过这些研究，我们了解到蚊子对主要由RNA干扰驱动的虫媒病毒感染具有天然的天然免疫防御能力。与此同时，我们认识到一些虫媒病毒已经进化出避免这种先天免疫的机制。关键是我们要确定蚊子抗病毒免疫和虫媒病毒之间的相互作用，以便更好地设计蚊媒疾病的控制方法。在这项提案中，我们将重点研究媒介蚊子，这种蚊子是人类种群中蚊媒传播疾病的主要原因。这项建议的具体目的如下：1)界定O‘nyong-Nyong病毒在冈比亚按蚊中传播的障碍。2)描述埃及伊蚊的感染和传播障碍；或辛德比斯病毒，并在两种不同的辛德比斯病毒株的背景下确定这些障碍。3)描述三带喙库蚊清除Sindbis病毒感染的中肠细胞的机制。

DESCRIPTION (provided by applicant): The re-emergence and global spread of mosquito-borne diseases is reducing the health of human and wildlife populations worldwide, and is an increasing drain on the world economy. In particular, mosquito borne viruses are re-emerging in endemic areas and rapidly spreading into new ranges across the globe (eg. West Nile virus in the Americas, Rift Valley fever virus in the Middle East, O'nyong-nyong virus in Africa). As a fundamental process for transmission, these arboviruses must replicate in mosquito gut tissues, disseminate throughout the mosquito body, and eventually infect the mosquito salivary glands. Using alphavirus transducing systems that express green fluorescent protein, we have been able to characterize routes of arboviral dissemination in mosquitoes. We have also made use of currently available genome data for Anopheles gambiae and Aedes aegypti mosquitoes, and with these data are beginning to characterize barriers to dissemination in vector mosquitoes. Through these studies, we are understanding that mosquitoes have natural innate immune defenses against arboviral infections that are primarily driven by RNA interference. At the same time, we are recognizing that some arboviruses have evolved mechanisms to avoid this innate immunity. It is critical that we characterize this interplay between mosquito anti-viral immunity and arboviruses to better design control methods for mosquito-borne disease. In this proposal, we focus our studies on vector mosquitoes that are responsible for the bulk of mosquito-borne disease in human populations. The specific aims of this proposal are as follows: 1) Define the barriers to O'nyong-nyong virus dissemination in Anopheles gambiae mosquitoes. 2) Characterize the infection and dissemination barriers ;or Sindbis viruses in Aedes aegypti mosquitoes and define these barriers in the context of two different Sindbis virus strains. 3) Characterize the mechanisms that Culex tritaeniorhynchus mosquitoes use to clear Sindbis virus-infected midgut cells.