PPG: HOST VIRUS INTERACTIONS IN HCoV-SARS INFECTIONS

描述（由申请人提供）： 人冠状病毒-SARS（SARS-CoV）是严重急性呼吸综合征（SARS）的唯一病原体。鉴于SARS-CoV感染引起的显著发病率和死亡率，我们了解这种感染的发病机制，以设计有效的疫苗和抗病毒治疗是很重要的。冠状病毒，特别是鼠冠状病毒，在过去的20年中得到了广泛的研究。在本PPG中，几位在冠状病毒和其他感染的发病机制和分子生物学以及宿主免疫反应方面拥有丰富经验的研究人员将研究SARS-CoV的发病机制。中心目标将是表征SARS-CoV与免疫系统和呼吸道靶细胞的相互作用。这一目标将在以下项目中进行研究。项目1-使用重组SARS-CoV和HCoV-OC 43（一种引起普通感冒的冠状病毒）建立SARS-CoV小鼠模型。检测SARS-CoV蛋白在冠状病毒感染背景下调节免疫应答的能力。项目2-确定SARS-CoV蛋白是否调节适应性免疫反应、树突状细胞功能或肺部病理，使用呼吸道病毒感染的良好表征的感染模型。开始利用HLA-A-2转基因小鼠鉴定SARS冠状病毒感染者的CD 8 T细胞表位。项目3-使用分化良好的人气道上皮细胞培养物研究SARS-CoV与气道上皮细胞的相互作用。目的探讨siRNA对SARS冠状病毒（SARS-CoV）致气道细胞感染的影响。项目4-研究负责与易感细胞结合的表面糖蛋白与其宿主细胞受体的相互作用，特别是与人气道细胞的相互作用。确定SARS-CoV S蛋白的致病关键结构域。这些项目都是相互关联的，将提供关于SARS冠状病毒发病机理的新信息，并将利用项目主任和联合主任的独特技能和专业知识。

DESCRIPTION (provided by applicant): The human coronavirus-SARS (SARS-CoV) is most likely the sole agent of Severe Acute Respiratory Syndrome (SARS). Given the significant morbidity and mortality caused by SARS-CoV infections, it is important that we understand the pathogenesis of this infection, in order to design effective vaccines and antiviral therapy. Coronaviruses, particularly murine coronaviruses, have been extensively studied in the past 20 years. In this PPG, several investigators with extensive experience in the pathogenesis and molecular biology of, and host immune response to, coronaviruses and other infections will investigate the pathogenesis of SARS-CoV. The central objective will be to characterize the interaction of SARS-CoV with the immune system and with target cells in the respiratory tract. This objective will be investigated in the following projects. Project 1-To develop a murine model of SARS-CoV using recombinant SARS-CoV and HCoV-OC43, a coronavirus that causes the common cold. To examine SARS-CoV proteins for their ability to modulate the immune response in the context of coronavirus infections. Project 2-To determine if SARS-CoV proteins modulate the adaptive immune response, dendritic cell function or lung pathology, using well characterized infectious models of respiratory viral infections. To begin to identify CD8 T cell epitopes recognized in humans infected with SARSCoV using HLA-A-2 transgenic mice. Project 3-To study interactions of SARS-CoV with airway epithelia using well differentiated cultures of human airway epithelia. To investigate the role of siRNA in modifying the airway cell infection caused by SARS-CoV. Project 4-To study interactions of the surface glycoprotein, responsible for binding to susceptible cells, with its host cell receptor, with particular reference to human airway cells. To identify domains of the SARS-CoV S protein that are critical in pathogenesis. These projects are all interrelated, will provide new information about the SARS-CoV pathogenesis and will take advantage of the unique skills and expertise of the project directors and co-directors.