Development of Murine Model for SARS-CoV Pathogenesis

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Severe Acute Respiratory Syndrome (SARS), a human disease with significant morbidity and mortality, was first recognized in late 2002. Within a few months, a human coronavirus, SARS-CoV was identified as the etiological agent for this disease. Little is known about the pathogenesis of this infection, but several features suggest that the disease is, in part, immunopathological. In contrast, much more is known about mechanisms of coronavirus-induced disease in animals. In specific, much has been learned about the immune-mediated demyelinating disease caused by mouse hepatitis virus, a murine coronavims, in large part because useful animal models are available for its study. At present, only non-human primates can be infected experimentally with SARS-CoV. While these animals will be useful for some studies, it would be extremely valuable if a small rodent model could be developed to answer questions about SARS-CoV pathogenesis and also to evaluate therapeutic interventions. Therefore the central objective of this project will be to develop and characterize an animal model for SARSCoV. This objective will be approached in the following specific aims. Specific aim 1. To develop methods to study the SARS-CoV genome, using targeted recombination. Since SARS-CoV does not appear to infect mice, recombinant SARS-CoV able to infect mice will be developed. Methodology will also be developed to introduce mutations into the human coronavirus, HCoV-OC43 (a cause of the common cold) since a mouse-adapted version of this virus is available. Specific aim 2. To characterize the pathogenesls of HCoV-OC43 and of recombinant SARS-CoV in mice. The clinical, pathological and immunological effects of infection of mice with these viruses will be investigated in this specific aim. Specific aim 3. To evaluate SARS-CoVspecific proteins for their role in pathogenesis in the mouse. Recombinant HCoV-OC43 expressing individual SARS-CoV will be characterized. Individual SARS-CoV-specific genes will be genetically disrupted in the context of the virus as part of this specific aim. These experiments will not only result in the development of a useful animal model for SARS-CoV, but will lead to identification of viral factors involved in immunomodulation.