Mechanism of murine coronavirus induced hepatitis

描述（由申请方提供）：人类丙型肝炎和B型肝炎病毒感染的特征为肝细胞坏死、炎症和肝癌发展。有证据表明，病毒诱导的肝炎与先天免疫应答效率低下有关;然而，导致疾病的确切细胞和分子机制仍然难以捉摸。我们建议使用一种小鼠冠状病毒，小鼠肝炎病毒（MHV），诱导肝炎病毒株特异性的方式，以评估病毒的遗传决定因素和宿主肝内先天免疫反应的发病机制。我们以前已经确定，刺突糖蛋白和MHV基因组3'三分之一的其他基因决定了在肝脏中复制的能力和相应的肝损伤严重程度。嗜肝性和非嗜肝性MHV毒株均可在原代肝细胞中复制;然而，非嗜肝性毒株在体内肝脏中无法复制。我们将使用嵌合重组病毒，诱导不同程度的肝炎，以测试假设，肝窦内皮细胞（LSEC）和/或枯否细胞限制进入和/或复制的非嗜肝性菌株的肝脏。用这些MHV毒株感染小鼠也将用于揭示MHV操纵宿主先天免疫应答以促进病毒复制的机制。将对受感染肝脏中免疫细胞的募集和活性以及细胞因子/趋化因子环境进行表征，以确定导致肝炎发病的因素。阐明MHV诱导脱髓鞘的机制将有助于理解人类肝炎，并从长远来看有助于设计抗病毒治疗。公共卫生相关性：肝炎是一种肝损伤的病理综合征，有多种原因，以不同程度的肝损伤为特征。人类慢性丙型肝炎和B型肝炎病毒感染导致肝损伤、炎症和肝癌的继发性发展。由于HCV和HBV感染而进行肝移植的必要性已成为严重的公共卫生问题;然而，目前还没有广泛有效的治疗方法来消除感染。据信，病毒引起的肝炎部分是由于免疫应答效率低下，但导致疾病的确切机制仍然难以捉摸。我们建议使用小鼠冠状病毒，小鼠肝炎病毒（MHV），诱导小鼠肝炎，以评估病毒和宿主因素的发病机制。我们将使用诱导不同水平肝炎的MHV毒株来检验肝窦内皮细胞和/或枯否细胞限制非嗜肝性毒株进入肝脏和/或在肝脏中复制的假设。用这些MHV毒株感染小鼠也将用于揭示MHV操纵宿主免疫应答以促进病毒复制的机制。对受感染肝脏中免疫细胞的募集和活性以及细胞因子/趋化因子环境的表征将揭示促成肝炎发病机制的因素。阐明MHV诱导脱髓鞘的机制将有助于理解人类肝炎，并从长远来看有助于设计抗病毒治疗

DESCRIPTION (provided by applicant): Hepatitis C and hepatitis B virus infections in humans are characterized by hepatocellular necrosis, inflammation, and development of hepatoma. There is evidence suggesting that virus-induced hepatitis is related to an inefficient innate immune response; however, the exact cellular and molecular mechanisms leading to disease remain elusive. We propose to use a murine coronavirus, mouse hepatitis virus (MHV), that induces hepatitis in a strain specific manner, to evaluate both viral genetic determinants and host intrahepatic innate immune responses underlying pathogenesis. We have previously established that the spike glycoprotein and other genes in the 3' one third of the MHV genome determine the ability to replicate in the liver and the corresponding severity of liver damage. Both hepatotropic and non-hepatotropic strains of MHV replicate in primary hepatocytes; however, non-hepatotropic strains fail to replicate in the liver in vivo. We will use chimeric recombinant viruses, that induce different levels of hepatitis to test the hypothesis that liver sinusoidal endothelial cells (LSEC) and/or Kupffer cells restrict entry and/or replication in the liver of non-hepatotropic strains. Infection of mice with these MHV strains will also be used to uncover mechanisms by which MHV manipulates the host innate immune responses to favor viral replication. Characterization of the recruitment and activity of immune cells and the cytokine/chemokine environment in the infected liver will be carried out to identify factors contributing to the pathogenesis of hepatitis. Elucidation of the mechanism of MHV induced demyelination will contribute to the understanding of hepatitis in humans and in the long term contribute to the design of anti-viral therapies. PUBLIC HEALTH RELEVANCE: Hepatitis is a pathological syndrome of liver injury that has several causes and is characterized by varying degrees of liver injury. Chronic hepatitis C and hepatitis B virus infections in humans result in liver damage, inflammation, and secondary development of liver cancer. The necessity for liver transplants as a result of HCV and HBV infection has become a serious public health issue; however, broadly effective therapies to eliminate infection are not currently available. It is believed that virus-induced hepatitis is in part due to an inefficient immune response, but the exact mechanisms leading to disease remain elusive. We propose to use a murine coronavirus, mouse hepatitis virus (MHV), which induces hepatitis in mice, to evaluate both viral and host factors underlying pathogenesis. We will use MHV strains, that induce different levels of hepatitis to test the hypothesis that liver sinusoidal endothelial cells and/or Kupffer cells restrict entry and/or replication in the liver of non- hepatotropic strains. Infection of mice with these MHV strains will also be used to uncover mechanisms by which MHV manipulates the host immune responses to favor viral replication. Characterization of the recruitment and activity of immune cells and the cytokine/chemokine environment in the infected liver will reveal factors contributing to the pathogenesis of hepatitis. Elucidation of the mechanism of MHV induced demyelination will contribute to the understanding of hepatitis in humans and in the long term contribute to the design of anti-viral therapies