The Sudden Acute Respiratory Syndrome (SARS) epidemic has spread to 30 countries and killed more than 800 people in the 7-month period from November 2002, to June 2003. The epidemic is a major public health emergency that has closed hospitals and schools and caused quarantines, travel advisories, and severe economic losses. No drugs or vaccines with proven efficacy are available to treat or prevent SARS. Little is known about the new, emerging coronavirus (SARS-CoV) that apparently jumped from wild animals into humans, and is now transmitted from person to person. The 6 principal investigators on this Program Project Grant have planned a coordinated analysis of the spike (S) glycoprotein on the envelope of the SARS-coronavirus to learn what species the virus can potentially infect, study how the S protein works as a molecular key to allow the virus to enter host cells, and develop new anti-viral drugs and vaccines to combat SARS-CoV. The first goals are to identify the cellular receptor for the virus, learn how it initiates virus infection, and develop antibodies and candidate anti-viral drugs that block virus infection of human cells. Dr. Holmes, who has studied receptors for other human and animal coronaviruses intensively, is the principal investigator of this Program Project Grant and Project 1. Dr. DeMartini (Project 2) has studied how viruses cause diseases of the lung in animals. He will identify animals susceptible to SARS-CoV infection, and study SARS lung pathology. Dr. Hodges (Project 3) and Dr. Wang (Project 4) will study the viral spike protein using biophysical, biochemical and functional assays with Dr. Holmes (Project 1), and by X-ray crystallography to learn what parts of the protein bind to the receptor, where antibodies target the spike, and how the spike causes membrane fusion. Dr. Wentworth (Project 5) and Dr. Mason (Project 6) will develop transgenic mice that express the human receptor for SARS-CoV and use them to learn how SARS-CoV causes disease. Mr. Shallow, (Administrative Core A) will coordinate the administration of the Projects that will be done in 5 institutions, and Dr. Holmes will coordinate the scientific interactions between the Projects. Dr. Pearson (Virus Core B) will work with the infectious SARS-CoV in the Biosafety Level 3 lab in collaboration with investigators from all of the other projects. Dr Gill (Protein Core C) will direct the synthesis and purification of viral spike proteins, receptor proteins and antibodies that are essential for each of these projects. This research will help to explain the origin of SARS-CoV, explain the pathology of SARS, develop candidate vaccines and drugs against SARS, and test them in new animal models for SARS.