Mechanism of murine coronavirus induced hepatitis

描述（由申请人提供）：人类丙型肝炎和乙型肝炎病毒感染的特征是肝细胞坏死、炎症和肝癌的发展。有证据表明，病毒引起的肝炎与先天免疫反应效率低下有关；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），以一种菌株特异性的方式诱导肝炎，来评估病毒遗传决定因素和宿主肝内先天免疫反应的潜在发病机制。我们之前已经确定，MHV基因组3' 1 / 3中的刺突糖蛋白和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。嗜肝型和非嗜肝型MHV在原代肝细胞中复制；然而，非嗜肝菌株在体内不能在肝脏中复制。我们将使用嵌合重组病毒，诱导不同程度的肝炎，以验证肝正弦内皮细胞（LSEC）和/或库普弗细胞限制非嗜肝菌株进入和/或复制肝脏的假设。用这些MHV毒株感染小鼠也将用于揭示MHV操纵宿主先天免疫反应以促进病毒复制的机制。将对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了解人类肝炎，并从长远来看有助于设计抗病毒治疗方法。公共卫生相关性：肝炎是肝损伤的病理综合征，有多种原因，特点是肝损伤程度不同。人类慢性丙型肝炎和乙型肝炎病毒感染会导致肝损伤、炎症和肝癌的继发发展。由于HCV和HBV感染而进行肝移植的必要性已成为一个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。人们认为，病毒性肝炎的部分原因是免疫反应效率低下，但导致疾病的确切机制仍然难以捉摸。我们建议使用一种小鼠冠状病毒，小鼠肝炎病毒（MHV），诱导小鼠肝炎，以评估病毒和宿主因素的潜在发病机制。我们将使用诱导不同程度肝炎的MHV毒株来检验肝窦内皮细胞和/或库普弗细胞限制非嗜肝毒株进入和/或复制的假设。用这些MHV毒株感染小鼠也将用于揭示MHV操纵宿主免疫反应以促进病毒复制的机制。对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肝炎发病机制的相关因素。阐明MHV诱导脱髓鞘的机制将有助于了解人类肝炎，并从长远来看有助于设计抗病毒治疗方法

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