Mosquito Immunity to Alphaviruses

描述（由申请人提供）：蚊媒疾病的重新出现和全球传播正在降低世界范围内人类和野生动物的健康，并日益消耗世界经济。特别是，蚊子传播的病毒正在流行地区重新出现，并迅速蔓延到全球各地的新范围。美洲的西尼罗病毒，中东的裂谷热病毒，非洲的奥尼昂-尼昂病毒)。作为传播的一个基本过程，这些虫媒病毒必须在蚊子肠道组织中复制，在蚊子全身传播，最终感染蚊子的唾液腺。利用表达绿色荧光蛋白的甲病毒转导系统，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获得的冈比亚按蚊和埃及伊蚊基因组数据，并利用这些数据开始确定媒介蚊子传播障碍的特征。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先天免疫防御。同时，我们认识到一些虫媒病毒已经进化出了避免这种先天免疫的机制。研究蚊子抗病毒免疫和虫媒病毒之间的相互作用，有助于更好地设计蚊媒疾病的控制方法，这一点至关重要。在本提案中，我们将研究重点放在对人类中大部分蚊媒疾病负责的媒介蚊子上。本提案的具体目的如下：1)确定冈比亚按蚊传播O'nyong-nyong病毒的障碍。2)表征感染和传播障碍；或埃及伊蚊中的信德比病毒，并在两种不同的信德比病毒株的背景下定义这些屏障。3)研究三带喙库蚊清除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.