Mechanisms of Antiviral Innate Immunity in Drosophila melanogaster

描述（由申请人提供）：麻疹、流感和艾滋病毒等病毒在世界范围内引起相当大的发病率。新出现的病毒是一种持续的威胁，因为它们的传播速度很快，而且有可能在开发出治疗方法之前引起广泛的疾病。我们对先天免疫系统对病毒的反应知之甚少。果蝇的免疫信号通路与人类、蠕虫和植物的免疫通路高度保守，使其成为一个很好的研究模型。我们建立了一种利用果蝇X病毒（DXV）感染果蝇的dsRNA birnavvirus来检测抗病毒先天免疫应答的系统。我们已经确定了Toll和RNAi途径对宿主防御很重要。从正向遗传筛选中，我们还发现了对病毒发病机制或抗病毒免疫反应重要的新突变。本建议的具体目的是：1。确定新的dxv易感突变体是否在Toll、RNAi或JAK/STAT通路中起作用。2. 研究过度活跃的免疫反应是如何对宿主造成伤害的。在DXV感染期间，过度活跃的免疫反应似乎对苍蝇有害。我们将确定Toll通路在这种反应中的可能作用，并对dxv耐药突变体进行表征，以潜在地确定该通路的负调节因子。3. 目的：通过定位克隆方法鉴定两个影响Toll或RNAi通路的新型抗病毒基因。总的来说，提出的实验可能会提供新的途径，或Toll或RNAi途径中对抗病毒免疫反应很重要的新基因。与公共卫生相关的病毒有许多品种，并成功地在人类中引起疾病；Toll通路和RNA干扰（RNAi）是宿主对抗病毒感染的两种手段。我们将鉴定对抗病毒免疫反应重要的新基因，并确定它们是否影响这两条途径。

DESCRIPTION (provided by applicant): Viruses such as measles, influenza, and HIV cause considerable morbidity worldwide. New emerging viruses are a constant threat because of the speed of their spread and their potential to cause widespread disease before therapies can be developed. Not much is known about innate immune responses against viruses. The immune signaling pathways in Drosophila are highly conserved with immune pathways in humans, worms, and plants, making it an excellent model for study. We have established a system to examine antiviral innate immune responses using the dsRNA birnavirus, Drosophila X virus (DXV) infection of Drosophila melanogaster. We have identified the Toll and RNAi pathways as important for host defense. From a forward genetic screen, we have also identified novel mutations important for viral pathogenesis or the antiviral immune response. The specific aims of this proposal are: 1. To determine whether the new DXV-susceptible mutants are acting in the Toll, RNAi, or JAK/STAT pathways. 2. To study how an overactive immune response can be damaging to the host. An overactive immune response appears to be harmful to the fly during DXV infection. We will determine the possible role of the Toll pathway in this response and characterize the DXV-resistant mutants to potentially identify negative regulators of this pathway. 3. To identify by map-based positional cloning two novel antiviral genes that affect either the Toll or RNAi pathway. Overall, the proposed experiments may give insight to new pathways, or new genes in Toll or RNAi pathways that are important for antiviral immune responses. PUBLIC HEALTH RELEVANCE Viruses come in many varieties and are successful in causing disease in humans; the Toll pathway and RNA interference (RNAi) are two means that the host uses to combat viral infection. We will identify novel genes important for the antiviral immune response and determine if they are affecting these two pathways.