Initiation and Regulation of Antiviral Innate Immunity

抗病毒先天免疫的启动和调节

• 批准号: 8223165
• 负责人: JONATHAN C KAGAN
• 金额: $ 43.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223165
• 关键词: Adaptor Signaling Protein; Address; Antiviral Agents; Bacterial Infections; Cells; Cellular biology; Cytosol; Data; Family; Gene Expression; Gene Expression Profile; Genes; Genome; Goals; Human; Immune; Immune response; Immunity; Infection; Initiator Codon; Interferon Type I; Interferons; Mammalian Cell; Mediating; Metabolic; Mitochondria; Motion; N-terminal; Natural Immunity; Organelles; Pattern recognition receptor; Physiological; Positioning Attribute; RNA; RNA Helicase; Reaction; Receptor Signaling; Regulation; Reovirus; Research Proposals; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Surveys; Therapeutic; Time; Variant; Vesicular stomatitis Indiana virus; Viral; Viral Interference; Virus; Virus Diseases; Virus Replication; Work; base; cell type; design; fighting; immune activation; influenzavirus; inhibitor/antagonist; innate immune function; innovation; novel; novel therapeutics; pathogen; peroxisome; prevent; public health relevance; receptor; receptor function; surveillance network; viral detection

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.

描述（由申请人提供）：该提案采用创新方法来解决先天免疫和细胞生物学中的一个关键问题：在受感染细胞内的何处检测到病毒？我们最近发现，除了线粒体之外，过氧化物酶体也是抗病毒先天免疫信号传导的信号平台。过氧化物酶体介导的信号传导通过 MAVS 的作用发生，MAVS 是一种接头蛋白，接收来自 RIG-I 的信号，RIG-I 是一种 RNA 解旋酶，可在细胞质中寻找含有 RNA 基因组的病毒。来自过氧化物酶体的 MAVS 信号传导诱导一种不寻常的不依赖干扰素的信号传导途径，激活抗病毒因子的快速表达。该信号通路被流感病毒、水泡性口炎病毒和哺乳动物呼肠孤病毒等多种病毒激活，并且能够限制病毒复制。基于这一发现，我们现在寻求（1）确定过氧化物酶体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于控制破坏 I 型干扰素表达的病毒至关重要，以及病毒限制如何已完成，并且（3）表征了一种新型的 RIG-I 信号负调节因子，该调节因子通过过氧化物酶体和线粒体发挥作用。我们提出的研究有可能深刻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疗法来操纵先天免疫信号分子的亚细胞定位，从而有助于触发或干扰免疫反应。） 公共卫生相关性：与细菌感染相比，治疗病毒感染的有效疗法严重缺乏。我们的研究计划旨在了解我们的抗病毒免疫反应是如何启动的，最终目标是利用我们的免疫防御来特异性消除感染。通过关注免疫激活的最早触发因素（检测进入我们细胞的病毒），我们希望发现可能适用于对抗所有感染的抗病毒防御策略。