Mechanisms of HBV-Induced Innate Immunity

乙型肝炎病毒诱导的先天免疫机制

基本信息

批准号：
10159072
负责人：
ALEEM SIDDIQUI
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-23 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159072
关键词：
Affect Antiviral Agents Apoptosis Apoptotic Applications Grants Attenuated Cell Death Cell Maintenance Chronic Chronic Hepatitis Chronic Hepatitis B Complex Data Dynamin Event Excision Fibrosis Gene Expression Genes Goals Hepatitis B Hepatitis B Virus Homeostasis Human Immune signaling Injury Innate Immune Response Interferons Investigation Lead Link Liver Mitochondria Liver diseases Lysine Maintenance Mediating Mediator of activation protein Metabolic Mitochondria Molecular Natural Immunity Oxidative Stress PINK1 gene Parkinson Disease Pathogenesis Phosphorylation Phosphotransferases Physiological Play Primary carcinoma of the liver cells Process Production Proteins Publishing Receptor Signaling Risk Factors Role Signal Transduction Signaling Molecule Signaling Protein TNF receptor-associated factor 3 Tretinoin Ubiquitination Virus Diseases Work chronic infection chronic liver injury cytochrome c innate immune pathways insight liver injury mitochondrial autophagy novel parkin gene/protein protein function recruit therapeutic target ubiquitin-protein ligase

项目摘要

Project Summary/Abstract Chronic Hepatitis B virus infections affect about 350 million people worldwide and constitute a significant risk factor for fibrosis and hepatocellular carcinoma (HCC). HBV alters mitochondrial dynamics. HBV has been shown to induce autophagy of mitochondria (Mitophagy) as evidenced by Parkin translocation to mitochondria. We propose to investigate a possible link between mitochondrial dynamics induced by HBV and innate immunity. HBV cripples host innate immunity to maintain chronic persistent infection. Here, we propose to investigate the molecular mechanisms of HBV- induced suppression of innate immune signaling from mitochondrial platform. The key player in this process is a mitochondrial antiviral signaling protein (MAVS). There is sufficient supporting information, which shows that Parkin, an E3 ubiquitin ligase, interacts with MAVS on the mitochondria and that Parkin causes the ubiquitination of MAVS. These investigations will elucidate how MAVS is targeted by Parkin in a supracomplex and affects downstream antiviral signaling of interferon synthesis. These interactions and ubiquitinations eventually cripple innate immunity. These studies will provide unique insights into molecular mechanisms of HBV-induced mitochondrial dynamics and its effects on altering host innate immune response and open new avenues of investigations in the elucidation of innate immune pathways.

项目概要/摘要慢性乙型肝炎病毒感染影响全球约 3.5 亿人，并构成纤维化和肝细胞癌（HCC）的重要危险因素。乙型肝炎病毒改变线粒体动力学。乙型肝炎病毒已被证明可诱导线粒体自噬（Mitophagy），如下所示：帕金易位至线粒体。我们建议研究线粒体之间可能的联系 HBV 和先天免疫诱导的动态变化。乙型肝炎病毒会削弱宿主的先天免疫力以维持慢性持续感染。在这里，我们建议研究 HBV-的分子机制。诱导抑制线粒体平台的先天免疫信号。这其中的关键人物过程是线粒体抗病毒信号蛋白（MAVS）。有足够的支撑信息显示 Parkin（一种 E3 泛素连接酶）与线粒体上的 MAVS 相互作用 Parkin 会导致 MAVS 泛素化。这些调查将阐明 MAVS 是如何超复合物中的 Parkin 靶向并影响干扰素的下游抗病毒信号传导合成。这些相互作用和泛素化最终会削弱先天免疫。这些研究将为 HBV 诱导的线粒体动力学的分子机制提供独特的见解，它对改变宿主先天免疫反应的影响并开辟了新的研究途径阐明先天免疫途径。