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和它们在开发治疗方法之前引起广泛疾病的潜力。对于针对病毒的先天免疫反应，我们所知不多。果蝇中的免疫信号通路与人类、蠕虫和植物中的免疫通路高度保守，使其成为研究的极好模型。我们建立了一个利用dsRNA双RNA病毒、果蝇X病毒（Drosophila X virus，DXV）感染果蝇的抗病毒天然免疫反应的检测系统。我们已经确定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应答重要的新突变。该提案的具体目标是：1.确定新的DXV易感突变体是否在Toll、RNAi或JAK/STAT途径中起作用。2.研究过度活跃的免疫反应如何损害宿主。一个过度活跃的免疫反应似乎是有害的苍蝇在DXV感染。我们将确定Toll途径在这种反应中的可能作用，并表征DXV抗性突变体，以潜在地识别该途径的负调节因子。3.通过图位克隆的方法鉴定两个新的影响Toll或RNAi途径的抗病毒基因。总的来说，拟议的实验可能会深入了解新的途径，或Toll或RNAi途径中的新基因，这些基因对抗病毒免疫反应很重要。公共卫生相关病毒有许多种类，并成功地在人类中引起疾病; Toll途径和RNA干扰（RNAi）是宿主用于对抗病毒感染的两种手段。我们将鉴定出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种途径。

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.