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

项目总结 许多肝脏病原体，如丙型肝炎病毒(丙型肝炎病毒)，已经建立了破坏宿主免疫的机制 应对措施，并建立持续感染。剖析这些机制并深入了解其影响因素 在肝脏中，促进病毒清除与慢性化的关系是出了名的困难。获取人体肝脏的途径 组织是有限的。唯一具有免疫活性的丙型肝炎病毒感染动物模型--黑猩猩--已经不再是 随时可供研究的。然而，我们最近成功地建立了第一个免疫系统- 丙型肝炎病毒相关病毒挪威鼠肝炎病毒(NrHV)的合格小鼠模型。我们的预赛 该模型的特征揭示了与丙型肝炎病毒感染显著的病毒学和免疫学相似之处。 在人类身上。这一进展现在开启了询问肝脏抗病毒免疫、宿主病毒的机会 嗜肝病毒的相互作用、病毒适应、免疫逃避策略和致病机制 前所未有的水平。在这项建议中，我们计划全面分析先天和适应性肝内 在体内感染肝炎病毒期间的免疫反应，并确定病毒清除的决定因素。这个 NrHV的自然宿主是老鼠。在免疫能力强的小鼠中，NrHV在感染几周后就会被清除。 因此，我们计划使这种病毒适应于小鼠，选择可以建立慢性化和 系统分析了寄主适应和免疫逃避的机制。通过NrHV感染 在北卡罗来纳州大学，我们将绘制宿主基因决定因素图 清除和坚持不懈。我们预计病毒适应小鼠宿主和 宿主基因筛查将满足在建立与病毒相关的强健模型方面尚未得到满足的重要需求 肝病。综上所述，我们提议的研究将使用多样化和多学科的方法来 嗜肝病毒体内感染研究的新进展。这些见解应该会为疫苗提供新的策略 病毒相关性肝病的发展或治疗。

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.