Analysis of the SARS Virus S glycoproteins

简介(申请人提供)：严重急性呼吸系统综合症(SARS)是一种迅速出现的传染病。SARS于2002年底在广东省中国首次发现，随后在世界各地迅速传播，香港、北京、广东和多伦多记录了主要的SARS病例。目前，台湾和多伦多报告了3000多例持续流行的病例。在整个人口中，SARS的死亡率似乎在5-10%之间，在65岁以上的患者中，老年人群的死亡率逐渐较高，达到近80%。一种新的冠状病毒已经被发现并被证明是导致SARS的原因。这种病毒被称为SARS相关冠状病毒(SCV)，是本研究的对象。冠状病毒是一种包膜的RNA病毒，依靠病毒粒子表面的糖蛋白进入宿主细胞。冠状病毒的Spike或S糖蛋白既负责识别宿主受体，也负责膜融合，将病毒运送到宿主细胞内。病毒糖蛋白也是体液免疫反应的靶标，S糖蛋白抗体有效地中和了其他冠状病毒。该应用程序的目标是开发一种全面分析SARS冠状病毒S糖蛋白的系统。为此，我们在特定的目标1中建议开发携带SCV尖峰的逆转录病毒假型，并利用这些假型开始对S糖蛋白进行初步分析。特异性目标2将使用多种独立的遗传和生化策略来鉴定脊髓灰质炎病毒S的细胞受体(S)。一旦确定受体(S)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显著增强我们对SARS病毒的了解，而且可能有助于SARS疫苗的开发，以及阻断SARS S功能或干扰S糖蛋白-受体相互作用的疗法的设计。

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.