Innate immune regulation during hepatitis C virus infection

丙型肝炎病毒感染期间的先天免疫调节

• 批准号: 8352240
• 负责人: Stacy Michelle Horner
• 金额: $ 16.14万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352240
• 关键词: Adaptor Signaling Protein; Automobile Driving; Biochemical; Cells; Cleaved cell; Complex; Coupled; Data; Detection; Disease; Epidemic; Fractionation; Goals; HIV; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Infection; Intracellular Membranes; Link; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Membrane; Microscopic; Mitochondria; Molecular; Molecular Chaperones; Natural Immunity; Organelles; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Play; Process; Proteins; Proteomics; RNA Viruses; RNA replication; Recombinants; Recruitment Activity; Regulation; Role; Signal Induction; Signal Transduction; Site; Synapses; Tertiary Protein Structure; Therapeutic; Vaccine Design; Viral; Virus; Virus Diseases; Virus Replication; Work; base; cytosolic receptor; design; insight; mortality; new therapeutic target; novel; novel therapeutics; novel vaccines; pathogen; peroxisome; prevent; programs; public health relevance; therapeutic vaccine; viral RNA

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a leading cause of liver disease and liver cancer. Nearly 170 million worldwide are chronically infected with HCV, and current treatment options are effective for only half of the infected. HCV persistence is mediated by the ability of the virus to evade the host innate immune response. While HCV RNA is sensed as foreign by the host cell cytosolic receptor RIG-I, the downstream signaling induced by this detection is suppressed by HCV NS3/4A protease cleavage of MAVS, the RIG-I signaling adaptor. MAVS is localized to mitochondria and peroxisomes, and I have recently found that it is also localized to mitochondrial- associated ER membranes (MAM), which link mitochondria and peroxisomes together into synapses during RIG-I activation. Further, I have found that the HCV NS3/4A protease targets these sites via the NS4A subunit of the protease complex for cleavage of MAVS on the MAM, and not the mitochondria. This data strongly implicates MAVS with MAM localization as the signaling active molecule that drives the innate immune response towards HCV. This proposal will explore the hypothesis that molecules targeted to the MAM during RIG-I pathway activation induce the formation of a MAVS signaling complex by using biochemical and proteomic studies that identify MAM-recruited molecules during the host innate immune response. In addition, the spatial-temporal regulation of NS4A targeting of the NS3/4A protease complex to the MAM for MAVS cleavage and immune evasion will be determined by identifying both the host cell factors and viral components that guide this targeting. These studies will provide valuable insights into the mechanism that activates the switch between the role of NS3/4A in HCV replication and innate immune control. Moreover, they will form the basis for studies to understand how MAM-targeting of MAVS by NS3/4A supports persistent HCV infection. These studies will determine how the MAM organizes both innate immune signaling and the HCV innate immune evasion program. A detailed understanding of these processes will have implications for therapeutic and vaccine design strategies to limit infection by HCV and other RNA viruses that are sensed by the RIG-I pathway.

描述（由申请人提供）：丙型肝炎病毒（HCV）是肝脏疾病和肝癌的主要原因。全世界有近1.7亿人慢性感染HCV，目前的治疗方案仅对一半感染者有效。HCV持续存在是由病毒逃避宿主先天免疫应答的能力介导的。虽然HCV RNA被宿主细胞胞质受体RIG-I感知为外源，但由该检测诱导的下游信号传导被HCV NS 3/4A蛋白酶切割MAVS（RIG-I信号传导衔接子）抑制。MAVS定位于线粒体和过氧化物酶体，并且我最近发现它也定位于线粒体相关的ER膜（MAM），其在RIG-I激活期间将线粒体和过氧化物酶体连接在一起形成突触。此外，我发现HCV NS 3/4A蛋白酶通过蛋白酶复合物的NS 4A亚基靶向这些位点，用于切割MAM上的MAVS，而不是线粒体。该数据强烈暗示MAVS与MAM定位作为驱动针对HCV的先天免疫应答的信号传导活性分子。该提案将探索以下假设：在RIG-I途径激活期间靶向MAM的分子通过使用在宿主先天免疫应答期间鉴定MAM募集分子的生物化学和蛋白质组学研究诱导MAVS信号复合物的形成。此外，NS 3/4A蛋白酶复合物的NS 4A靶向MAM以进行MAVS切割和免疫逃避的时空调节将通过鉴定指导该靶向的宿主细胞因子和病毒组分来确定。这些研究将为深入了解NS 3/4A在HCV复制和先天免疫控制中的作用之间的转换机制提供有价值的见解。此外，它们将成为研究NS 3/4A如何靶向MAVS的MAM支持持续HCV感染的基础。这些研究将确定MAM如何组织先天免疫信号传导和HCV先天免疫逃避程序。对这些过程的详细了解将对治疗和疫苗设计策略产生影响，以限制由RIG-I途径感测的HCV和其他RNA病毒的感染。