Initiation and Regulation of Antiviral Innate Immunity

描述（由申请人提供）：该提案采用一种创新的方法来解决先天免疫和细胞生物学中的一个关键问题：在感染细胞的哪里检测到病毒？我们最近发现，除了线粒体外，过氧化物酶体也是抗病毒先天免疫信号的信号平台。过氧化物酶体介导的信号通过MAVS的作用发生，MAVS是一种接收rig - 1信号的衔接蛋白，rig - 1是一种RNA解旋酶，用于调查含有RNA基因组的病毒的细胞质。来自过氧化物酶体的MAVS信号诱导了一个不寻常的干扰素非依赖性信号通路，激活了抗病毒因子的快速表达。该信号通路可被多种病毒激活，如流感病毒、水泡性口炎病毒和哺乳动物呼肠孤病毒，并能够限制病毒复制。基于这一发现，我们现在寻求(1)确定来自过氧化物酶体的信号传导如何导致抗病毒免疫的启动，(2)确定过氧化物酶体信号传导是否对破坏I型干扰素表达的病毒的控制至关重要，以及病毒限制是如何完成的，以及(3)表征来自过氧化物酶体和线粒体的RIG-I信号传导的一种新的负调节因子。我们提出的研究有可能深刻地改变我们对哺乳动物细胞内抗病毒免疫如何组织的看法。这项工作可能有助于设计新的治疗方法来操纵先天免疫信号分子的亚细胞定位，帮助触发或干扰免疫反应。

DESCRIPTION (provided by applicant): This proposal takes an innovative approach to address a critical question in innate immunity and cell biology: Where within infected cells are viruses detected? We have recently discovered that in addition to mitochondria, peroxisomes are signaling platforms for antiviral innate immune signaling. Peroxisome-mediated signaling occurs through the actions MAVS, an adaptor protein that receives signals from RIG-I, an RNA helicase that surveys the cytosol for viruses containing RNA genomes. MAVS signaling from peroxisomes induces an unusual interferon-independent signaling pathway that activates the rapid expression of antiviral factors. This signaling pathway is activated by diverse viruses such as influenza virus, vesicular stomatitis virus and mammalian reovirus, and is capable of restricting viral replication. Based on this discovery, we now seek to (1) determine how signaling from peroxisomes leads to the initiation of antiviral immunity, (2) determine if peroxisomal signaling is critical for the control of viruses that disrupt type I interferon expression, and how viral restriction is accomplished, and (3) characterize a novel negative regulator of RIG-I signaling that functions from peroxisomes and mitochondria. Our proposed studies have the potential to profoundly change our view of how antiviral immunity is organized within mammalian cells. This work may facilitate the design of novel therapeutics to manipulate the subcellular positioning of innate immune signaling molecules, helping to either trigger or interfere with an immune reaction.) PUBLIC HEALTH RELEVANCE: Compared to bacterial infections, there is an alarming lack of effective therapeutics to treat viral infections. Our research proposal seeks to understand how our antiviral immune responses are set into motion, with the ultimate goal of harnessing our immune defenses to specifically eliminate infections. By focusing on the earliest triggers of immune activation (the detection of viruses that enter our cells) we hope to uncover antiviral defense strategies that might be applicable to fight all infections.