Center for the Study of Innate Immunity to HCV Infection

HCV 感染先天免疫研究中心

• 批准号: 8648990
• 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/8648990
• 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，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，一个是行政核心项目，一个是临床核心项目，它们被整合到一个研究项目中，旨在确定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。丙型肝炎病毒是一个重大的公共卫生问题，全世界有近2亿人感染。大多数暴露于丙型肝炎病毒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。丙型肝炎病毒感染用干扰素（IFN）治疗，但只有50%的患者对治疗有反应。因此，为了改善丙型肝炎病毒感染和治疗结果，有必要了解丙型肝炎病毒持久性和干扰素作用的基础。我们的研究已经确定了特定的病毒和宿主过程，这些过程控制着肝脏对HCV的先天免疫反应，是指导HCV感染和治疗结果的主要决定因素。因此，本U19项目的研究集中在理解控制HCV感染的肝脏先天免疫程序的共同主题上，并将研究病毒和宿主控制的肝脏先天免疫防御决定HCV感染和IFN治疗结果的总体假设。为了研究这一假设，我们的项目将包括以下研究：项目1)确定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，并在感染期间介导效应和逃避反应；项目2)确定HCV/宿主相互作用，驱动肝脏IFN产生和肝细胞与肝树突状细胞之间的反应，以控制HCV感染；项目3)确定肝脏microRNA效应物在HCV患者肝脏先天免疫调节及IFN治疗应答中的作用。U19项目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得到促进。总的来说，拟议的项目是独特的，重点是了解控制肝脏先天免疫的病毒/宿主界面，从而控制HCV感染的结果。这些研究的结果将为指导设计旨在调节HCV感染的改进治疗策略和疫苗方法提供新的见解。

项目成果

Impact of the autophagy machinery on hepatitis C virus infection.

• DOI: 10.3390/v3081342
• 发表时间: 2011-08
• 期刊: Viruses
• 作者: Dreux M;Chisari FV
• 通讯作者: Chisari FV

Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver.

• DOI: 10.1002/hep.26770
• 发表时间: 2014-06
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Wieland, Stefan;Makowska, Zuzanna;Campana, Benedetta;Calabrese, Diego;Dill, Michael T.;Chung, Josan;Chisari, Francis V.;Heim, Markus H.
• 通讯作者: Heim, Markus H.

Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity.

• DOI: 10.1016/j.chom.2012.08.010
• 发表时间: 2012-10-18
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Dreux M;Garaigorta U;Boyd B;Décembre E;Chung J;Whitten-Bauer C;Wieland S;Chisari FV
• 通讯作者: Chisari FV

Sterol-izing innate immunity.

• DOI: 10.1016/j.immuni.2013.01.002
• 发表时间: 2013-01
• 期刊: Immunity
• 影响因子: 32.4
• 作者: C. Wilkins;M. Gale