Project Summary: The Severe Acute Respiratory Syndrome, caused by a novel coronavlrus (SARS-CoV), resulted in substantial morbidity and mortality in 2002-2003. With the lack of recurrence of SARS, research efforts to understand pathogenesis and develop an effective vaccine have largely halted. However, coronaviruses similar to SARS-CoV have been identified in bats and other animal populations in China, making recurrence of SARS a possibility. Thus, we believe that efforts need to continue to understand pathogenesis and to develop vaccines and anti-viral therapies. In this PPG, several investigators with extensive experience in the pathogenesis, molecular biology and immunology of coronavirus infections will work together to better understand the interaction of SARS-CoV with the host respiratory tract and to develop novel approaches to preventing and treating SARS-CoV infections. These objectives will be investigated in the following projects. Project 1 will investigate severe disease in young BALB/c and aged BALB/c and C57BL/6 mice infected with mouse-adapted SARS-CoV and in SARS-CoV-infected mice that are transgenic for the human cellular receptor (angiotensin converting enzyme 2, hACE2). Project 2 will focus on the role of ACE2 signaling in pathogenesis. This project will also investigate the role of ACE2 by comparing cells and mice infected with SARS-CoV and HCoV-NL63, a common cold virus that also uses ACE2 to enter cells but does not cause severe disease. Project 3 will investigate the mechanism of action of two novel anti-virus therapies (rhesus theta defensin and griffithsin) and will investigate the role of ACE2 shedding in pathogenesis. Project 4 will develop and evaluate live attenuated SARS-CoV vaccines, based on the observation that virus deleted in the small envelope protein is viable, immunogenic and safe. All of the projects will use the Virology/Animal Models Core, which will engineer and propagate recombinant SARSCoV and will also analyze infected mice. Using the Core for these purposes will ensure reproducibility and ensure most effective use of our resources. These projects are all interrelated, will provide new information about SAR-CoV pathogenesis and will take advantage of the unique skills and expertise of the project directors.