Analysis of the SARS Virus S glycoproteins

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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.