Crosstalk in RNA Mediated Innate Antiviral Responses

描述（由申请人提供）：流感病毒株的毒力与它们脱离细胞先天抗病毒反应的能力有关。目前针对新出现的流感病毒株的一种抗病毒治疗策略涉及使用RNA沉默技术，这种方法在治疗流感病毒感染方面已经显示出很大的希望。本研究旨在以流感病毒感染为手段，探索细胞内双链RNA （dsRNA）触发的两种先天抗病毒系统之间的相互作用和串扰。RNA干扰（RNAi）是一种内在的dsrna介导的基因沉默系统，是植物和动物细胞基因调控的核心。RNAi是一种有效的先天抗病毒系统，对植物和低等动物的病原体防御至关重要，并已被用作人类疾病的治疗策略。在脊椎动物中，I型干扰素诱导一种有效的细胞抗病毒反应。IFN基因起源于大约2.5亿年前鸟类分化后的一个祖先的复制。RNA沉默的抗病毒作用在脊椎动物中不太明显，基于dsRNA的先天免疫反应基因可能来自RNA沉默系统的组成部分。这一提议的核心假设是，这两个古老的dsRNA加工系统在功能上整合在人类细胞中细胞先天抗病毒免疫反应的调节中。这两个RNA处理系统之间的相互依赖和交叉调控是本探索性应用的重点。在流感病毒感染的背景下，提出了两个互补的特定目的来测试干扰素抗病毒信号和RNA沉默之间的联系。

DESCRIPTION (provided by applicant): The virulence of influenza virus strains has been linked to their ability to disengage cellular innate antiviral responses. One current antiviral therapeutic strategy for emerging influenza strains involves the use of RNA silencing techniques, and this approach has already shown great promise in the treatment of influenza virus infections. This proposal is designed to use influenza virus infections as a means to explore the interaction and crosstalk between two innate antiviral systems triggered by intracellular double stranded RNA (dsRNA). RNA interference (RNAi) is an intrinsic dsRNA-mediated gene silencing system that is central to cellular gene regulation in the plant and animal kingdoms. RNAi is a potent innate antiviral system central to pathogen defenses in plants and lower animals, and has been harnessed as a therapeutic strategy for human diseases. In vertebrates, the type I interferons induce a potent cellular antiviral response. The IFN genes originated by duplication of a progenitor after the divergence of birds approximately 250 million years ago. The antiviral contributions of RNA silencing are less pronounced in vertebrates, and dsRNA based innate immune response genes may have arisen from components of the RNA silencing system. It is the central hypothesis underlying this proposal is that these two ancient dsRNA processing systems are functionally integrated in the regulation of cellular innate antiviral immune responses in human cells. The interdependence and cross-regulation between these two RNA processing systems is the focus of this exploratory application. Two complementary specific aims are proposed to test the link between IFN antiviral signaling and RNA silencing in the context of influenza virus infections.