Initiation and Regulation of Antiviral Innate Immunity

抗病毒先天免疫的启动和调节

基本信息

批准号：
8824865
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
项目类别：
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/8824865
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 Health 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 receptor receptor function surveillance network viral detection

项目摘要

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.)

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关键问题：在感染细胞中检测到病毒的位置？我们最近发现，除线粒体外，过氧化物酶体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动作MAVS（一种接收来自RIG-I的信号的动作MAV），它是RIG-I的信号，RIG-I是一种RNA解旋酶，该RNA解旋酶调查了含有RNA基因组病毒的细胞质。来自过氧化物酶体的MAVS信号传导诱导非寻常的干扰素信号传导途径，从而激活抗病毒因子的快速表达。该信号通路被多种病毒（例如流感病毒，囊肿性气孔病毒和哺乳动物依膜病毒）激活，并能够限制病毒复制。基于这一发现，我们现在寻求（1）确定过氧化物酶体的信号传导如何导致抗病毒免疫的开始，（2）确定过氧化物酶体信号是否对于破坏I型干扰素表达的病毒的控制以及如何完成病毒限制的病毒的控制至关重要，并且（3）表征新型的焦点症状和焦点的负调控器。我们提出的研究有可能深刻地改变我们对哺乳动物细胞中抗病毒免疫如何组织的看法。这项工作可能有助于设计新型治疗剂，以操纵先天免疫信号分子的亚细胞定位，有助于触发或干扰免疫反应。）