The recent outbreak of Severe Acute Respiratory Syndrome (SARS) is a striking example of a potentially devastating emerging infectious disease. Although the initial SARS outbreak was contained through public health efforts, the epidemiology of respiratory virus infections in humans suggests that re-emergence of this disease is a distinct possibility. Unfortunately, current antiviral therapies did not prove effective in SARS patients. Thus, developing an effective vaccine is likely the best strategy for limiting this disease in the human population. The evidence to date is that SARS is caused by a human coronavirus (SARS-CoV), and the sequence of this virus has been determined. However, as useful as the molecular information may be for understanding the relationship of SARS-CoV to other coronaviruses, it is not sufficient to predict how the virus behaves in vivo and what elements of the virus will be targets for effective vaccination. Studies with respiratory virus infections suggest that disease pathogenesis may result from virus-mediated lysis of infected cells, the host immune response, or both. While limited, early studies with SARS patients reveal low, but constant levels of virus in the serum, during disease progression. This suggests that the immune system is contributing to the pathogenesis of disease. Alternatively, or in addition, the virus may evade the immune system in order to persist. Experimental systems to address SARS-CoV pathogenesis have not been described and very little is known about the immune response to SARS-CoV. In large part, the progress from molecular characterization of human viruses to vaccines is hampered by the lack of suitable small animal models for studies of pathogenesis and immune responses. The long-term goal of this project is to develop a mouse model to provide information on the pathogenesis and immune response to SARS-CoV that will be useful in designing vaccines to protect the population. We will address this long-term goal with the following specific aims:
Aim 1. Characterize the specificity of the anti-SARS-CoV human CD8+ T cell response with HLA-A*201-transgenic mice and generate SARS-CoV protein-specific monoclonal antibodies.
Aim 2. Determine if SARS-CoV proteins modulate adaptive immunity in the context of infection.
Aim 3. Determine if SARS-CoV proteins modulate DC and NK immunity in the context of infection.
Aim 4. Determine if SARS-CoV proteins modulate lung pathology in the context of infection.
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