The long-term goal of this project is to understand the virus-host interactions that are critical to the disease caused by the coronavirus associated with Severe Acute Respiratory Syndrome in humans (SARS-CoV). This understanding is required to develop potential treatments, and inhibitors of the disease that is caused by this emerging pathogen. It is believed that the outbreak of Severe Acute Respiratory Syndrome began in the Guangdong Province of China in November, 2002. Since its emergence, SARS-CoV has infected thousands of people throughout the globe. SARS-CoV is a novel coronavirus that is readily isolated from the lungs, throat swabs, and feces specimens of infected people. Serological studies indicate that SARS-CoV had not infected humans in the USA or Hong Kong prior to the current outbreak, illustrating that it is a new human pathogen. The SARS-CoV outbreak in people is extraordinary because of the high morbidity and mortality associated with infection. It is clear that animal models of the disease caused by SARS-CoV are required to combat this emerging pathogen, which has both epidemic and pandemic potential. To our knowledge SARS-CoV has been inoculated into mice, pigs, chickens, and primates. To date, only monkeys have been infected by the virus. The limitation of infection to only very closely related species, such as humans and monkeys, is not surprising, because the interaction between the coronavirus attachment protein and the host cell receptor is very precise. Virus-receptor interactions are responsible for the species specificity and pathogenesis of many different coronaviruses that infect people, pigs, cats, dogs, and mice. Although monkeys, and potentially other animals, will be important to study the virus, a mouse model for SARS-CoV is crucial for the evaluation of antiviral treatments, vaccine strategies, and studies of pathogenesis. However, data suggests that normal mice are not permissive to infection by SARS-CoV. Our objective is to develop a small animal model for SARS-CoV by creating transgenic mice that express the receptor(s) utilized by the virus. To accomplish this goal; we will create transgenic mice that express the receptor(s) for SARS-CoV, examine the susceptibility of these transgenic mice to SARS-CoV, and analyze the prevention or treatment of SARS-CoV infection in the transgenic mice. Addressing these aims will produce an excellent small animal model of SARS-CoV infection in people, as well as, expand our understandin 9 of processes important in pathogenesis, and the emer0ence of new viruses in humans.