The SARS epidemic is caused by a novel coronavirus (SARS-CoV) that jumped to humans from a wild animal host. Identifying the natural host of SARS-CoV and other susceptible animals is crucial to control SARS in humans. SARS-CoV infects the respiratory and intestinal tract but there is little specific information on target cells for viral replication or damage. The objectives of this proposal are to discover the role of the expression of the receptor for SARS-CoV and its interaction with the viral S glycoprotein in determining the host range, tissue tropism, and mechanisms of lung disease in SARS. Our hypothesis is that infection of macrophages plays a central role in the pathogenesis of SARS. The specific aims are: 1) Determine the SARS-CoV host range and tissue tropism by studying binding of virus and viral S glycoprotein to isolated cell membranes of a wide variety of animal species. We will use solid phase binding assays to study host range and tissue tropism and a virus overlay protein binding assay to determine the molecular mass of the receptor in positive species; 2) Determine whether SARS-CoV in vitro infection of human macrophage and dendritic cells leads to their activation, apoptosis, and dysregulated cytokine production. This aim will require titration of virus, detection of virus infected cells by immunological techniques, and analysis of cytokine/chemokine production by RNA and protein arrays, and 3) Establish transgenic mice for the SARS- CoV receptor as models for SARS to study target tissues for viral infection, replication, and tissue damage. We will analyze lung cell phenotypes and apoptosis by flow cytometry, and evaluate of tissue damage by histopathology and confocal microscopy. This information and the availability of a mouse model to evaluate therapeutic interventions will lead to improved diagnosis, treatment and control of SARS. Our research will identify the actual animal host for SARS-CoV in Asia and potential animal hosts for SARS-CoV in the United States. Finally, the data will provide information on the mechanism of species jumping.