Mechanisms of Antiviral Innate Immunity in Drosophila melanogaster

麻疹、流感和艾滋病毒等病毒在世界范围内造成相当大的发病率。新的 新出现的病毒是一个持续的威胁，因为它们的传播速度和潜力 在开发治疗方法之前导致广泛的疾病。人们对此知之甚少 针对病毒的先天免疫反应。果蝇的免疫信号通路有 在人类、蠕虫和植物的免疫途径中高度保守，使其成为极好的 学习用的模型。我们已经建立了一个系统来检查抗病毒的先天免疫反应 利用双链RNA小核糖核酸病毒，果蝇X病毒(Dxv)感染黑腹果蝇。 我们已经确定Toll和RNAi通路对宿主防御很重要。从一个前锋 在基因筛查中，我们还发现了对病毒致病机制重要的新突变 抗病毒免疫反应。这项建议的具体目的是：1.研究 抗病毒反应中的Toll和RNAi途径。我们将调查这些是否 通路相互作用或独立作用，并决定dsrna是否可能是致病因素。 激活苍蝇体内抗病毒免疫反应的决定因素。2.确定是否 新的DXV敏感突变体正在Toll、RNAi或JAK/STAT途径中发挥作用。3.至 确定过度活跃的免疫反应是否在DXV中被抑制- 表现出高滴度DXV的抗药性突变体。过度活跃的免疫反应似乎 在DXV感染期间对苍蝇有害。我们将确定通行费可能发挥的作用 并对DXV抗性突变体进行鉴定以潜在地鉴定 这一途径的负调节因子。4.通过基于地图的位置克隆识别两个 影响Toll或RNAi途径的新的抗病毒基因。整体而言，建议的 实验可能会让我们深入了解新的通路，或Toll或RNAi通路中的新基因 对抗病毒免疫反应很重要。病毒有许多变种，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的两种手段 感染。我们将描述这两条通路的作用，并识别新的基因 对抗病毒免疫反应很重要。

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 study the roles of the Toll and RNAi pathways in the antiviral response. We will investigate whether these pathways interact or act independently, and determine whether dsRNA may be the pathogenic determinant that activates the antiviral immune response in flies. 2. To determine whether the new DXV-susceptible mutants are acting in the Toll, RNAi, or JAK/STAT pathways. 3. To determine whether an overactive immune response is being suppressed in the DXV- resistant mutants that show high titers of DXV. 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. 4. 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. 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 characterize the role of these two pathways and identify novel genes important for the antiviral immune response.