Analysis of the SARS Virus S glycoproteins

描述（由申请人提供）：严重急性呼吸系统综合征（SARS）是一种迅速出现的传染病。SARS于2002年底在中国广东省首次被发现，随后迅速在世界各地传播，香港、北京、广东和多伦多记录了主要的SARS病例。目前，台湾和多伦多报告的流行病例已超过3000例。似乎SARS的死亡率在整个人口中介于5-10%之间，在年龄较大的人群中，死亡率逐渐升高，在65岁以上的患者中达到近80%。一种新型冠状病毒已被发现并被证明是SARS的罪魁祸首。这种病毒被称为SARS相关冠状病毒（SCV）是本研究的对象。冠状病毒是有包膜的RNA病毒，其依赖于病毒粒子表面上的糖蛋白进入宿主细胞。冠状病毒的刺突或S糖蛋白负责识别宿主受体，也负责膜融合以将病毒递送到宿主细胞内。病毒糖蛋白也是体液免疫反应的靶点，S糖蛋白抗体可有效中和其他冠状病毒。本申请的目的是开发一个系统，用于SARS冠状病毒S糖蛋白的综合分析。为此，我们在具体目标1中建议开发携带SCV刺突的逆转录病毒假型，并利用这些假型开始S糖蛋白的初步分析。具体目标2将使用各种独立的遗传和生物化学策略鉴定SCV S的细胞受体。一旦确定了受体及其与S糖蛋白的相互作用，将进行研究。实现这些特定目标不仅将大大提高我们对SARS病毒的认识，而且可能有助于SARS疫苗的开发和阻断SARS S功能或干扰S糖蛋白-受体相互作用的治疗方法的设计。

DESCRIPTION (provided by applicant): Severe Acute Respiratory Syndrome (SARS) is a rapidly emerging infectious disease. First observed in the Guangdong Province in China in late 2002, SARS has spread rapidly around the world with predominant SARS cases documented in Hong Kong, Beijing, Guangdong, and Toronto. At present well over 3000 cases are reported with ongoing epidemics in Taiwan and Toronto. It appears that the mortality rate for SARS is between 5-10% for the entire population with progressively higher rates in older age groups reaching nearly 80% in patients over 65 years. A novel coronavirus has been identified and shown to be responsible for SARS. This virus called SARS-associated coronavirus (SCV) is the object of this study. Coronaviruses are enveloped RNA viruses that depend upon glycoproteins on the virion surface to enter host cells. The Spike or S glycoprotein of coronaviruses is responsible for both recognition of host receptors and also for membrane fusion to deliver the virus inside the host cell. Viral glycoproteins are also the targets for humoral immune responses and antibodies to S glycoproteins effectively neutralize other coronaviruses. The goal of this application is to develop a system for comprehensive analysis of the SARS coronavirus S glycoproteins. Toward that end, we propose in Specific Aim 1 to develop retroviral pseudotypes that carry the SCV spike and to utilize these pseudotypes to begin a preliminary analysis of the S glycoprotein. Specific Aim 2 will identify the cellular receptor(s) for SCV S using a variety of independent genetic and biochemical strategies. Once identified the receptor(s) and its interaction with S glycoproteins will be studied. Achieving these Specific Aims will not only significantly enhance our understanding of the SARS virus, but will likely aid in the development of vaccines for SARS and in design of therapeutics that block SARS S function or interfere with S glycoprotein-receptor interactions.