Mechanisms of Antiviral Innate Immunity in Drosophila melanogaster

描述(申请人提供)：麻疹、流感和艾滋病毒等病毒在全球范围内造成相当大的发病率。新出现的病毒是一个持续的威胁，因为它们的传播速度很快，而且在开发治疗方法之前有可能导致广泛的疾病。人们对病毒的先天免疫反应知之甚少。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。我们已经建立了一种利用dsRNA双核糖核酸病毒，果蝇X病毒(DXV)感染黑腹果蝇来检测抗病毒天然免疫反应的系统。我们已经确定Toll和RNAi通路对宿主防御很重要。从正向基因筛查，我们还发现了对病毒致病或抗病毒免疫反应重要的新突变。这项建议的具体目的是：1.确定新的DXV敏感突变体是否作用于Toll、RNAi或JAK/STAT途径。2.研究过度活跃的免疫反应如何对宿主造成损害。在感染DXV期间，过度活跃的免疫反应似乎对苍蝇有害。我们将确定Toll途径在这一反应中的可能作用，并对DXV抗性突变体进行特征分析，以潜在地识别该途径的负调控因子。3.通过基于图谱的定位克隆，鉴定影响Toll或RNAi途径的两个新的抗病毒基因。总体而言，拟议的实验可能会深入了解新的途径，或Toll或RNAi途径中对抗病毒免疫反应重要的新基因。与公共卫生相关的病毒有许多种类，并成功地在人类身上引起疾病；Toll途径和RNA干扰(RNAi)是宿主用来对抗病毒感染的两种手段。我们将识别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.