The "corona" surrounding the virus particles that cause Severe Acute Respiratory Syndrome (SARS) is one of the hallmarks of coronaviruses, a group of large, enveloped RNA viruses that cause important respiratory and enteric diseases of humans, domestic animals and poultry. The corona is composed of large viral spike (S) glycoproteins that determine the host range and tissue tropism of the virus, affect virus virulence and serve as potential targets for antiviral vaccines and drugs. In Project 1, we will study the structure and functions of the S glycoprotein of the coronavirus that causes SARS (SARS-CoV). We will first identify human cell lines and tissues that are susceptible to infection with SARS-CoV, and then isolate a host cell macromolecule, probably a protein, that the S protein of SARS-CoV uses as a receptor to initiate infection. We will determine whether antibodies against the spike or receptor protein and/or small molecules that mimic the spike or receptor can block infection of cells by SARS-CoV. We will evaluate them as lead compounds for development of novel drugs or vaccines for treatment or prevention of SARS. After S proteins on virions bind to the receptor on the host cell membrane, the spikes undergo a programmed series of conformational changes that lead to membrane fusion and virus infection. We will characterize these changes and develop antibodies or drugs that block virus binding to receptors and fusion of SARS-CoV with cellular membranes as additional novel drugs for treating or preventing SARS. With Projects 3 and 4 we will study the structures and functions of S protein and its receptor, and compare the receptor with homologous molecules from animals (Project 2) to discover the molecular basis for the species specificity and tissue tropism of SARS-CoV infection. We will provide cDNA clones encoding the receptor to our colleagues in Projects 5 and 6, who will express the human receptor in transgenic mice to develop small animal models for studies on SARS pathogenesis and for evaluation of candidate drugs and vaccines against SARS.