A Genetic Analysis of Pneumotropism and Pneumovirulence in an MHV-1 Model of Sars

描述（由申请人提供）：本提案的目的是利用一种新的SARS啮齿动物模型来描述导致严重急性呼吸综合征（SARS）的病毒基因。SARS在全球感染了8,000多人，700多人死亡。我们建议使用我们小组开发的SARS MHV-1感染小鼠模型来鉴定导致这种严重肺部疾病的冠状病毒基因。本研究的第一个目的是利用反向遗传学方法，在我们的模型中研究结构蛋白刺突蛋白（S）、基质蛋白（E）和核衣壳蛋白（N）以及非结构辅助蛋白在SARS样肺炎发病机制中的作用。这些研究将采用靶向重组方法。嵌合MHV-1/非嗜肺重组病毒将用于确定靶向肺和发展SARS样肺病所需的MHV-1基因。在第二个目标中，我们将调查的假设，即ACE 2受体结合域的SARS-CoV刺突蛋白（Srbd）有助于SARS的发病机制，废除肺保护作用的ACE 2除了它的作用，在病毒附着到细胞。将分离MHV-1/SARS-Srbd重组体，并确定其增强毒力和在其他MHV-1抗性小鼠中引起致死性SARS样肺病的能力。这些研究将确定MHV-1基因是必要的和/或足够的独特的SARS样病理由这种病毒诱导，并评估的作用，SARS-CoV Srbd的发病机制独立的作用，作为病毒附着蛋白在小鼠模型中的SARS。公共卫生相关性：本研究的目的是利用一种新的啮齿类动物SARS模型来描述导致严重急性呼吸综合征（SARS）的病毒基因。SARS在全球感染了8,000多人，700多人死亡。我们将使用一种相关的冠状病毒，小鼠肝炎病毒1型（MHV-1），它在小鼠中产生一种类似SARS的疾病。我们使用这种新开发的SARS小鼠模型来鉴定导致这种严重肺部疾病的冠状病毒基因。这些信息应该有助于我们进一步了解SARS和其他冠状病毒肺部感染，并可能为开发未来治疗这些疾病的方法提供基础。

DESCRIPTION (provided by applicant): The goal of this proposal is to delineate the viral genes that lead to severe acute respiratory syndrome (SARS) utilizing a novel rodent model of SARS. SARS infected over 8,000 persons globally with over 700 deaths. We propose to use a MHV-1 infected mouse model of SARS developed by our group to identify coronavirus genes that contribute to this severe pulmonary disease. The first aim of the research will utilize reverse genetics to examine the roles of structural proteins spike (S), matrix (E) and nucleocapsid (N) proteins and non-structural accessory proteins in the pathogenesis of SARS-like pneumonitis in our model. These studies will employ a targeted recombination approach. Chimeric MHV-1/non-pneumotropic recombinant viruses will be used to determine the MHV-1 genes necessary for targeting to the lung and for the development of SARS like pulmonary disease. In the second aim we will investigate the hypothesis that the ACE2 receptor binding domain of the SARS-CoV spike protein (Srbd) contributes to SARS pathogenesis by abrogating the pneumoprotective effect of ACE2 in addition to its role in viral attachment to cells. MHV-1/SARS-Srbd recombinants will be isolated and their ability to enhance virulence and cause lethal SARS-like pulmonary disease in otherwise MHV-1 resistant mice will be determined. These studies will identify MHV-1 genes that are necessary and/or sufficient for the unique SARS-like pathology induced by this virus, and assess the role of the SARS-CoV Srbd in pathogenesis independent of its role as a viral attachment protein in a mouse model of SARS. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to delineate the viral genes that lead to severe acute respiratory syndrome (SARS) utilizing a novel rodent model of SARS. SARS infected over 8,000 persons globally with over 700 deaths. We will use a related coronavirus, mouse hepatitis virus type 1 (MHV-1), that produces a disease in mice that mimics SARS. We use this newly developed mouse model of SARS to identify coronavirus genes that contribute to this severe pulmonary disease. This information should be useful in advancing our understanding of SARS and other coronavirus pulmonary infections and may provide a basis for developing future therapeutic approaches to these diseases.