Analysis of immunity, viral adaptation and pathogenesis in a new mouse model of HCV-related rodent hepacivirus infection

HCV相关啮齿动物肝炎病毒感染新小鼠模型的免疫、病毒适应和发病机制分析

基本信息

批准号：
9332881
负责人：
Charles M Rice
金额：
$ 70.39万
依托单位：
ROCKEFELLER UNIVERSITY
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：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332881
关键词：
Acute Adaptive Immune System Affect Age Alcohols Animal Model Antigens Automobile Driving Basic Science CD8-Positive T-Lymphocytes Cells Characteristics Chronic Chronic viral hepatitis Cirrhosis Comorbidity Development Disease Environment Family Flavivirus Flow Cytometry Genes Genetic Genetic Determinism Genetic Screening HCV Animal Models Hepacivirus Hepatic Hepatitis C Hepatocyte Human Immune Immune Evasion Immune response Immune system Immunity Immunocompetent Immunologics Immunology Inbred BALB C Mice Infection Interferon Type I Kinetics Laboratory mice Lead Light Liver Liver diseases MHC Class I Genes Maps Medical Research Modeling Molecular Biology Mouse Strains Mus Natural Immunity Obesity Outcome Pan Genus Pathogenesis Pathology Predisposition Primary carcinoma of the liver cells RNA Virus Infections RNA Viruses Rattus Rattus norvegicus Research Resistance Resolution Resources Rodent Role Signal Transduction Systems Biology T-Lymphocyte T-Lymphocyte Epitopes Tissues Vaccines Variant Viral Virus Virus Diseases adaptive immune response adaptive immunity antiviral immunity base exhaustion in vivo innovation insight interdisciplinary approach intrahepatic liver development liver injury mouse model novel pathogen tool transcriptome sequencing vaccination strategy vaccine development virology virus host interaction virus pathogenesis

项目摘要

Project summary Many liver pathogens, like hepatitis C virus (HCV), have established mechanisms to subvert the host immune response and to establish persistent infection. Dissecting these mechanisms and gaining insight into factors that contribute to viral clearance versus chronicity in the liver is notoriously difficult. Access to human liver tissue is limited. The only immunocompetent animal model of HCV infection, the chimpanzee, is no longer readily available for research. However, we have recently succeeded in establishing the first immune- competent mouse model of an HCV-related virus, Norway rat hepacivirus (NrHV). Our preliminary characterization of this model revealed significant virological and immunological similarities with HCV infection in humans. This advance now opens the opportunity to interrogate hepatic antiviral immunity, host-virus interactions, viral adaptation, immune evasion strategies and pathogenesis of a hepatotropic virus at an unprecedented level. In this proposal we plan to comprehensively analyze innate and adaptive intrahepatic immune responses during hepacivirus infection in vivo and to define determinants of viral clearance. The natural host of NrHV is the rat. In immune-competent mice NrHV is cleared after several weeks of infection. Thus we plan to adapt this virus to the mouse, select for viral variants that can establish chronicity and systematically analyze mechanisms of host-adaptation and immune evasion. Through NrHV infection of the genetically diverse Collaborative Cross mouse colony at UNC, we will map the host genetic determinants of clearance and persistence. We anticipate that combined approaches of viral adaptation to the murine host and a host genetic screen will meet an important unmet need in establishing a robust model of virus-associated liver disease. Taken together, our proposed research will use a diverse and multidisciplinary approach to shed new light on hepatotropic virus infection in vivo. These insights should provide new strategies for vaccine development or treatment of virus-associated liver disease.

项目摘要许多肝炎病毒（HCV）等许多肝病病原体已经建立了颠覆宿主免疫的机制反应并建立持续感染。解剖这些机制并深入了解因素众所周知，这种导致病毒清除与肝脏中的慢性造成的贡献很困难。进入人肝组织有限。 HCV感染的唯一免疫能力动物模型，黑猩猩，不再是随时可用于研究。但是，我们最近成功建立了第一个免疫力 HCV相关病毒的合格小鼠模型，挪威大鼠肝病毒（NRHV）。我们的初步该模型的表征揭示了与HCV感染显着的病毒学和免疫学相似性在人类中。现在，这项进步打开了审问肝病病毒免疫的机会，宿主病毒相互作用，病毒适应，免疫逃避策略和肝病病毒的发病机理空前的水平。在此提案中，我们计划全面分析先天和适应性肝内体内肝病毒感染期间的免疫反应并定义病毒清除的决定因素。这 NRHV的天然寄主是大鼠。在感染数周后，在免疫能力的小鼠中清除了NRHV。因此，我们计划使该病毒适应小鼠，选择可以建立慢性和的病毒变体系统地分析宿主适应和免疫逃避的机制。通过NRHV感染在UNC的基因合作跨小鼠菌落中，我们将映射的宿主遗传决定因素清除和持久性。我们预计病毒适应对鼠寄主的合并方法和宿主遗传屏幕将满足建立与病毒相关的强大模型的重要未满足的需求肝病。综上所述，我们拟议的研究将使用多种多样的多学科方法在体内感染肝病感染的新光。这些见解应为疫苗提供新的策略病毒相关肝病的发展或治疗。