Center for the Study of Innate Immunity to HCV Infection

HCV 感染先天免疫研究中心

• 批准号: 8245840
• 负责人: Michael Gale
• 金额: $ 85.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245840
• 关键词: Achievement; Antiviral Agents; Antiviral Therapy; Applications Grants; Area; Basic Science; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Coupled; Critical Pathways; Dendritic Cells; Future; Gene Expression; Genes; Genetic Determinism; Genome; Genotype; Goals; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune; Immune response; Immunity; Immunobiology; Immunology; Immunotherapy; In Vitro; Infection; Interferon Type II; Interferon-alpha; Interferons; Learning; Link; Liver; Liver Failure; Liver diseases; Mediating; MicroRNAs; Modeling; Molecular; Natural Immunity; Outcome; Pan Genus; Pathway interactions; Patient Care; Patients; Pattern; Pattern Recognition; Peptide Hydrolases; Play; Process; Production; Proteins; Public Health; RNA; Reporting; Research; Research Institute; Research Personnel; Research Project Grants; Role; Signal Transduction; Structure-Activity Relationship; System; Therapeutic; Translational Research; Treatment outcome; Universities; Vaccines; Viral; Viral hepatitis; Virus; Washington; Work; base; chronic liver disease; design; functional genomics; improved; in vivo; insight; interferon therapy; medical schools; medical specialties; novel; pathogen; programs; receptor; response; therapy outcome; translational approach; translational study; virology; virus host interaction

DESCRIPTION (provided by applicant): This U19 research grant application responds to the Hepatitis C Cooperative Research Center (HC CRC) RFA to establish the Center for the Study of Innate Immunity to Hepatitis C virus (HCV) Infection. The Center is comprised of three projects, an Administrative Core, and a Clinical Core, integrated into a Program of study aimed at defining the innate immune mechanisms that control hepatitis C virus infection and the response to antiviral therapy. HCV is a major public health problem, infecting nearly 200 million people worldwide. Most people exposed to HCV go on to develop a chronic infection that often associates with liver disease or liver failure, and can result in death. Infection with HCV is treated with alpha interferon (IFN)- based therapy but only 50% of patients respond to treatment. Thus, there is a great need to understand the basis of HCV persistence and IFN actions in order to improve HCV Infection and treatment outcome. Our studies have defined specific virus and host processes that control the hepatic innate immune response against HCV as major determinants directing the outcome of HCV infection and treatment. The studies in this U19 Program are therefore focused on the common theme of understanding hepatic innate immune programs that control HCV infection, and will investigate the overarching hypothesis that virus and host control of innate hepatic immune defenses define the outcome of HCV infection and IFN therapy. To investigate this hypothesis our Program will include studies to: Project 1) Define the viral and host genetic determinants that confer pathogen recognition of HCV, regulate hepatic innate immune triggering, and that mediate effector and evasion responses during infection; Project 2) Define the HCV/host interactions that drive hepatic IFN production and response between hepatocytes and liver dendritic cells to control HCV infection; Project 3) Determine the role of hepatic microRNA effectors in regulating hepatic innate immunity and the response to IFN therapy in HCV patients. The management for the U19 Program will be conducted though an Administrative Core. The research materials support and clinical data support for this Program will be facilitated through a Clinical Core. Overall, the proposed projects are unique to focus on understanding the virus/host interface that controls hepatic innate immunity to govern the outcome of HCV infection. Results from these studies will provide novel insights to guide the design of improved therapeutic strategies and vaccine approaches aimed at modulating HCV infection. RELEVANCE: Hepatitis C virus (HCV) infects the liver and causes liver disease and death. There are nearly 200 million people with HCV infection in the world but the molecular mechanisms that support infection are not understood. Our studies have now linked HCV infection with virus and host processes that control innate immunity of the liver. We propose to investigate these processes of innate immunity in order to understand how innate immune programs of the liver can control HCV infection and the outcome of antiviral therapy. Results from these studies will provide novel insights to guide the design of improved therapeutic strategies and vaccine approaches aimed at controlling HCV infection and associated liver disease. PROJECT 1: Title: Mechanisms of Pathogen Recognition and Innate Immune Control of Hepatitis C Virus Project Leader: GALE, M. PROJECT 1 DESCRIPTION (provided by applicant): Project 1 comprises a component of our Hepatitis C virus Cooperative Research Center (HC CRC) U19 application. The focus of Project 1 is to understand the molecular mechanisms by which HCV is recognized by the host cell as a foreign pathogen to trigger immunity against infection, and to learn how HCV evades these processes to mediate infection outcome among clinical cases of HCV. HCV is a hepatotropic virus that mediates a persistent infection and chronic liver disease in millions of people worldwide. HCV persistence is associated with viral strategies to evade innate immune defenses and a¿ interferon (IFN) immune actions that normally limit Infection. We have identified HCV genome RNA and the cellular RIG-I protein as the viral pathogen-associated molecular pattern (PAMP) and host pathogen recognition receptor that interact to trigger the expression of RIG-l-responsive genes that serve as immune effectors to control innate immunity and HCV infection. We have found that HCV can disrupt innate immune signaling via the actions of the viral NS3/4A protease, thus providing an evasion strategy that allows HCV to persist. We hypothesize that viral PAMP signaling and gene expression mediated through the RIG-I pathway are critical determinants controlling hepatic immunity and the outcome of HCV infection. Our studies are therefore deigned 1) Define the structure-function relationship of viral PAMP recognition by RIG-I among clinical isolates of HCV, 2) Identify the RIG-l-responsive genes of the liver that regulate HCV infection, and 3) Determine the function of NS3/4A to regulate the RIG-I pathway among clinical cases of HCV infected with different viral genotypes. Our studies are linked with the U19 Clinical Core, and Projects 2 and 3 to feature translational approaches aimed at defining the virus-host interface that controls hepatic innate immunity and HCV infection.

描述（由申请人提供）：本 U19 研究资助申请响应丙型肝炎合作研究中心 (HC CRC) RFA 的要求，建立丙型肝炎病毒 (HCV) 感染先天免疫研究中心。该中心由三个项目组成，即行政核心和临床核心，整合到一个研究计划中，旨在确定控制丙型肝炎病毒感染和抗病毒治疗反应的先天免疫机制。 HCV 是一个重大的公共卫生问题，感染全球近 2 亿人。大多数接触丙肝病毒的人会继续发展为慢性感染，这种感染通常与肝病或肝功能衰竭有关，并可能导致死亡。 HCV 感染采用基于 α 干扰素 (IFN) 的疗法进行治疗，但只有 50% 的患者对治疗有反应。因此，非常需要了解 HCV 持续存在的基础和 IFN 作用，以改善 HCV 感染和治疗结果。我们的研究已将控制针对 HCV 的肝脏先天免疫反应的特定病毒和宿主过程定义为指导 HCV 感染和治疗结果的主要决定因素。因此，本 U19 计划的研究重点是了解控制 HCV 感染的肝脏先天免疫程序这一共同主题，并将研究病毒和宿主对肝脏先天免疫防御的控制决定 HCV 感染和 IFN 治疗结果的总体假设。为了研究这一假设，我们的计划将包括以下研究： 项目 1) 定义病毒和宿主遗传决定因素，这些决定因素赋予 HCV 病原体识别、调节肝脏先天免疫触发以及在感染期间介导效应和逃避反应；项目2）定义HCV/宿主相互作用，驱动肝细胞和肝树突状细胞之间的肝脏干扰素产生和反应，以控制HCV感染；项目3）确定肝脏microRNA效应子在调节肝脏先天免疫和HCV患者对IFN治疗的反应中的作用。 U19 计划的管理将通过行政核心进行。该计划的研究材料支持和临床数据支持将通过临床核心提供便利。总体而言，拟议项目的独特之处在于，重点了解控制肝脏先天免疫以控制 HCV 感染结果的病毒/宿主界面。这些研究的结果将为指导旨在调节丙型肝炎病毒感染的改进治疗策略和疫苗方法的设计提供新的见解。 相关性：丙型肝炎病毒 (HCV) 感染肝脏并导致肝脏疾病和死亡。世界上有近 2 亿人感染 HCV，但支持感染的分子机制尚不清楚。我们的研究现已将丙型肝炎病毒感染与控制肝脏先天免疫的病毒和宿主过程联系起来。我们建议研究先天免疫的这些过程，以了解肝脏的先天免疫程序如何控制 HCV 感染和抗病毒治疗的结果。这些研究的结果将为指导旨在控制丙型肝炎病毒感染和相关肝病的改进治疗策略和疫苗方法的设计提供新的见解。 项目1： 题目：丙型肝炎病毒的病原体识别和先天免疫控制机制 项目负责人：盖尔，M. 项目 1 描述（由申请人提供）：项目 1 包含我们的丙型肝炎病毒合作研究中心 (HC CRC) U19 应用程序的一部分。项目1的重点是了解HCV被宿主细胞识别为外来病原体以触发感染免疫的分子机制，并了解HCV如何逃避这些过程以介导HCV临床病例中的感染结果。 HCV 是一种嗜肝病毒，可介导全球数百万人的持续感染和慢性肝病。 HCV 的持续存在与病毒逃避先天免疫防御的策略以及通常限制感染的干扰素 (IFN) 免疫作用有关。我们已经鉴定出 HCV 基因组 RNA 和细胞 RIG-I 蛋白作为病毒病原体相关分子模式 (PAMP) 和宿主病原体识别受体，它们相互作用触发 RIG-1 反应基因的表达，这些基因作为免疫效应子控制先天免疫和 HCV 感染。我们发现 HCV 可以通过病毒 NS3/4A 蛋白酶的作用破坏先天免疫信号，从而提供一种逃避策略，使 HCV 能够持续存在。我们假设通过 RIG-I 途径介导的病毒 PAMP 信号传导和基因表达是控制肝脏免疫和 HCV 感染结果的关键决定因素。因此，我们的研究旨在：1）确定HCV临床分离株中RIG-I识别病毒PAMP的结构-功能关系，2）鉴定调节HCV感染的肝脏RIG-1反应基因，以及3）确定NS3/4A在感染不同病毒基因型的HCV临床病例中调节RIG-I通路的功能。我们的研究与 U19 临床核心以及项目 2 和 3 相关，以转化方法为特色，旨在定义控制肝脏先天免疫和 HCV 感染的病毒-宿主界面。