The JAK-STAT pathway in anti-dengue defense

描述（由申请人提供）：蚊子利用各种策略来对抗病原体，包括病毒。免疫学研究的长期目标是在分子水平上阐明蚊子媒介埃及伊蚊对一系列病毒病原体感染的免疫反应，包括那些可能被用作生物恐怖主义制剂的病原体。近年来，登革热已成为最严重的媒介传播病毒性疾病之一。登革热病毒在蚊子载体中传播的分子生物学在很大程度上是未知的，但是现在可用的基因组序列、反向遗传、转基因和功能基因组学工具提供了更详细地剖析蚊子的抗病毒防御系统的手段。在这个建议中，我们将应用这些工具来表征的含义。埃及人JAK-STAT先天免疫途径在防御登革热病毒中的作用。我们已经表明，蚊子正在利用JAK-STAT免疫途径通过基于RNAi的方法来限制登革热病毒感染。我们现在将使用基于转基因方法的更强大的方法来扩展这一发现，并更好地表征多个时间点和组织对病毒感染的JAK-STAT途径免疫反应。在具体目标1中，我们将产生和分子表征有条件激活JAK-STAT途径的转基因蚊子系。在具体目标2中，我们将研究重组激活的JAK-STAT途径的时空抗登革热活性，以更好地评估该防御系统在开发登革热控制策略中的潜在用途。 公共卫生相关性：尽管登革热流行率急剧上升，但令人惊讶的是，人们对病毒与蚊子媒介相互作用的分子生物学和遗传基础知之甚少。这项研究计划旨在利用转基因技术对蚊子对病毒感染的免疫防御进行分子表征，这些免疫防御由JAK-STAT途径控制。这项研究产生的知识可以有助于开发登革热和其他病毒（如黄热病和西奈尔斯病毒）的控制方法。

DESCRIPTION (provided by applicant): Mosquitoes utilize a variety of strategies to combat pathogens, including viruses. The long-term goal of the PIs research is to elucidate, at the molecular level, the immune responses of the mosquito vector Aedes aegypti to infection with a range of viral pathogens, including those that could be used as agents for bioterrorism. In recent years, dengue fever has emerged as one of the most serious vector-borne viral diseases. The molecular biology of dengue virus propagation in the mosquito vector is largely unknown, but the genome sequence, reverse genetic, transgenic and functional genomics tools that are now available provide a means of dissecting the mosquito's anti-viral defense systems in greater detail. In this proposal, we will apply these tools to characterize the implication of the Ae. aegypti JAK-STAT innate immune pathway in defense against the dengue virus. We have already showed that the mosquito is employing the JAK-STAT immune pathways to limit dengue virus infection through RNAi - based approaches. We will now use more powerful approaches, based on transgenic methodology, to expand on this finding and better characterize the JAK-STAT pathway immune responses to virus infection at multiple time points and tissues. In Specific Aim 1 we will generate and molecularly characterize the genetically modified mosquito lines that conditionally activate the JAK-STAT pathway. In Specific Aim 2 we will investigate the spatio- temporal anti-dengue activity of the recombinantly activated JAK-STAT pathway to better assess the potential use of this defense system for the development of dengue control strategies. PUBLIC HEALTH RELEVANCE: Despite the dramatic surge in dengue prevalence, surprisingly little is known about the molecular biology and genetic basis of the virus interactions with the mosquito vectors that enable transmission. This research proposal aims at the molecular characterization of the mosquito's immune defenses against virus infection that are controlled by the JAK-STAT pathway using transgenic technologies. The knowledge generated from this study can contribute to the development of control methods for dengue and other viruses such as yellow fever and West Niles viruses.