Center for the Study of Innate Immunity to HCV Infection

HCV 感染先天免疫研究中心

• 批准号: 8050597
• 负责人: Michael Gale
• 金额: $ 84.71万
• 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/8050597
• 关键词: Center; Study; Innate; Immunity; HCV

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，以建立丙型肝炎病毒（HCV）感染先天免疫研究中心。该中心由三个项目组成，一个是行政核心，一个是临床核心，整合到一个研究计划中，旨在定义控制丙型肝炎病毒感染的先天免疫机制和对抗病毒治疗的反应。HCV是一个主要的公共卫生问题，感染了全球近2亿人。大多数暴露于HCV的人会发展成慢性感染，通常与肝脏疾病或肝功能衰竭有关，并可能导致死亡。HCV感染用基于α干扰素（IFN）的疗法治疗，但只有50%的患者对治疗有反应。因此，非常需要了解HCV持久性和IFN作用的基础，以改善HCV感染和治疗结果。我们的研究已经确定了特定的病毒和宿主过程，控制肝脏对HCV的先天免疫反应作为主要的决定因素，指导HCV感染和治疗的结果。因此，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的共同主题，并将调查先天肝脏免疫防御的病毒和宿主控制定义HCV感染和IFN治疗结果的总体假设。为了研究这一假设，我们的项目将包括以下研究：项目1）定义赋予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的病毒和宿主遗传决定因素;项目2）定义驱动肝细胞和肝树突状细胞之间的肝IFN产生和反应以控制HCV感染的HCV/宿主相互作用;项目3）确定肝脏microRNA效应物在调节HCV患者肝脏先天免疫和对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。本项目的研究材料支持和临床数据支持将通过临床核心来促进。总体而言，拟议的项目是独特的，重点是了解病毒/宿主界面，控制肝脏先天免疫，以管理HCV感染的结果。这些研究的结果将提供新的见解，以指导设计改进的治疗策略和疫苗的方法，旨在调节HCV感染。 相关性：丙型肝炎病毒（HCV）感染肝脏，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。我们的研究已经将HCV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。这些研究的结果将提供新的见解，以指导旨在控制HCV感染和相关肝脏疾病的改进治疗策略和疫苗方法的设计。 项目1： 题目：丙型肝炎病毒的病原体识别和天然免疫控制机制 项目负责人：GALE，M. 项目1描述（由申请人提供）：项目1包括我们的丙型肝炎病毒合作研究中心（HC CRC）U19申请的组成部分。项目1的重点是了解HCV被宿主细胞识别为外源病原体以触发抗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临床病例的感染结果。HCV是一种嗜肝病毒，介导全世界数百万人的持续感染和慢性肝病。HCV持续存在与病毒逃避先天免疫防御的策略和通常限制感染的干扰素（IFN）免疫作用有关。我们已经鉴定了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，其相互作用以触发RIG-I应答基因的表达，所述RIG-I应答基因作为免疫效应物以控制先天免疫和HCV感染。我们已经发现，HCV可以通过病毒NS 3/4A蛋白酶的作用破坏先天免疫信号传导，从而提供一种逃避策略，使HCV持续存在。我们推测，病毒PAMP信号和基因表达介导的RIG-I途径是控制肝脏免疫和HCV感染的结果的关键决定因素。因此，我们的研究被设计为1）在HCV的临床分离株中确定RIG-I识别病毒PAMP的结构-功能关系，2）鉴定调节HCV感染的肝脏的RIG-I应答基因，和3）确定NS 3/4A在不同病毒基因型感染的HCV的临床病例中调节RIG-I途径的功能。我们的研究与U19临床核心以及项目2和项目3相关联，旨在定义控制肝脏先天免疫和HCV感染的病毒-宿主界面的翻译方法。