The Host Response to Hepatitis C Virus

宿主对丙型肝炎病毒的反应

• 批准号: 9234470
• 负责人: Michael Gale
• 金额: $ 50.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234470
• 关键词: Ablation; Acetylation; Acute; Acute Hepatitis C; Adaptor Signaling Protein; Alphavirus; Antiviral Agents; Binding; Biochemical; Biochemical Genetics; Biological Models; Cell Culture Techniques; Cells; Cessation of life; Chronic; Chronic Hepatitis C; Cleaved cell; Cytosine; Cytosol; DNA Viruses; Enterovirus; Exhibits; Exposure to; Gene Expression; Genes; Genome; Goals; HDAC6 gene; HIV; Hepatic; Hepatitis B; Hepatitis C; Histone Deacetylase; Human Papillomavirus; Immune; Immune response; Immune signaling; In Vitro; Infection; Infection Control; Innate Immune Response; Interferons; Ligand Binding; Ligands; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Membrane; Mitochondria; Modeling; Modification; Molecular; Mus; NF-kappa B; Natural Immunity; Outcome; Pathway interactions; Patients; Pattern; Pattern Recognition; Peptide Hydrolases; Process; Production; Proteins; Public Health; RNA Binding; RNA Virus Infections; RNA Viruses; Regulation; Research; Retinoic Acid Binding; Role; Signal Transduction; Simplexvirus; Site; TRIM25 gene; Testing; Text; Tretinoin; Uridine; Variant; Viral; Viral Genome; Virus; Virus Diseases; Virus Replication; antiviral immunity; cofactor; genetic approach; immunoregulation; in vivo; microbial disease; pathogen; prevent; programs; protein complex; public health relevance; receptor; sensor; transmission process; tripolyphosphate; viral RNA; virus genetics; virus host interaction

 DESCRIPTION (provided by applicant): The virus/host interactions that control the transition from acute to chronic virus infection are not well understood. Hepatitis C virus (HCV) is a model RNA virus of chronic infection and is a contemporary public health problem. This application continues our focus on defining the molecular mechanisms of hepatic innate immunity that impart acute to chronic HCV infection outcome. We have shown that retinoic acid inducible gene-I (RIG-I) initiates the hepatic innate immune response upon recognition and binding of the pathogen associated molecular pattern (PAMP) consisting of 5' triphosphate and the poly-uridine/cytosine (pU/UC) motif within the HCV RNA. During acute infection this recognition of the transmission/founder (T/F) viral genome by RIG-I results in its modification and activation to bind the MAVS adaptor protein on mitochondria-associated membranes (MAM) and signal hepatic innate immune defenses that restrict infection. Our preliminary studies now reveal that T/F genomes from patients exhibit remarkable variation within their pU/UC motif, and that this variation imparts differential recognition and binding by RIG-I that allows escape from non-self-recognition. Moreover, we have found that signaling by RIG-I is dependent on formation of a RIG-I translocon protein complex that facilitates RIG-I cytosol-to-membrane translocation for MAVS interaction and signaling on the MAM. Our studies now reveal that these activities are governed by the reversible acteylation of RIG-I, and that this process is likely controlled through the HDAC6 protein as a RIG-I cofactor of innate immunity. We show that HCV evades hepatic innate immunity via MAM targeting by the NS3/4A viral protease to cleave MAVS and disrupt RIG-I signaling, thereby facilitating chronic infection, and this action is dependent on stable NS3/4A- MAVS interaction on the MAM. Disruption of this interaction restores innate immunity to prevent acute to chronic HCV transition. We hypothesize that regulation of the RIG-I pathway and hepatic innate immunity are major determinants controlling the acute to chronic transition of HCV infection. We will therefore conduct studies to: 1) Define the RIG-I/PAMP interactions of pathogen recognition and differential innate immune signaling from T/F genomes during acute HCV infection; 2) Determine the role of RIG-I acetylation in translocon assembly and function; 3) Identify the NS3/4A/MAVS interface that mediates interaction to control the RIG-I pathway.

 描述（由申请人提供）：控制从急性病毒感染到慢性病毒感染的转变的病毒/宿主相互作用尚不清楚。丙型肝炎病毒（HCV）是慢性感染的模型RNA病毒，并且是当代的公共卫生问题。应用继续我们的重点是确定肝脏先天免疫的分子机制，该机制可导致急性至慢性 HCV 感染结果。我们已经证明，视黄酸诱导基因-I (RIG-I) 在识别后启动肝脏先天免疫反应。以及由 5' 三磷酸和 HCV RNA 内的多聚尿苷/胞嘧啶 (pU/UC) 基序组成的病原体相关分子模式 (PAMP) 的结合，在急性感染期间，这种对传播/创始人 (T/F) 病毒的识别。 RIG-I 基因组导致其修饰和激活，以结合线粒体相关膜 (MAM) 上的 MAVS 接头蛋白，并发出限制感染的肝脏先天免疫防御信号。它们的 pU/UC 基序内存在变异，并且这种变异赋予 RIG-I 的差异识别和结合，从而允许逃避非自我识别。此外，我们发现 RIG-I 的信号传导依赖于 RIG-I 的形成。 I 易位子蛋白复合物，促进 RIG-I 胞质到膜易位，以实现 MAVS 相互作用和 MAM 上的信号传导。我们的研究现在表明，这些活性是由 RIG-I 的可逆乙酰化控制的，并且该过程是可能通过 HDAC6 蛋白作为先天免疫的 RIG-I 辅助因子 我们发现，HCV 通过 NS3/4A 病毒蛋白酶靶向 MAM 来裂解 MAVS 并破坏 RIG-I 信号传导，从而逃避肝脏先天免疫，从而促进慢性感染。依赖于 MAM 上稳定的 NS3/4A-MAVS 相互作用，这种相互作用的破坏可恢复先天免疫，以防止急性到慢性 HCV 的转变。 RIG-I 途径和肝脏先天免疫是控制 HCV 感染急性向慢性转变的主要决定因素，因此我们将进行研究：1) 定义病原体识别的 RIG-I/PAMP 相互作用以及 T/F 的差异先天免疫信号。急性 HCV 感染期间的基因组；2) 确定 RIG-I 乙酰化在易位子组装和功能中的作用；3) 识别介导相互作用以控制RIG-I 途径。