Severe Acute Respiratory Syndrome (SARS) is a coronavirus-induced human respiratory disease with a 10% mortality. Mortality is especially high in aged populations. Using a mouse-adapted version of SARSCoV (MAI 5 virus) that causes severe disease in BALB/c mice, we previously showed that the initial immune response is activated suboptimally in infected mice and this resulted, in turn, in a delayed anti-virus T cell response. We also found that depletion of lung inhibitory macrophages, important for maintaining homeostasis in the uninfected lung, or adoptive transfer of activated dendritic cells resulted in activation of the pulmonary immune response, an enhanced anti-virus T cell response and complete protection from severe clinical disease. The central objectives of this proposal are to determine whether enhancement of the anti-virus T cell response, in the absence of other interventions, is sufficient to protect young BALB/c mice from severe disease and to investigate whether quantitiative and qualitative defects also contribute to disease in aged mice, which like older humans, are more susceptible to infection than young animals. These objectives will be approached in the following specific aims:
Specific aim 1. To determine if enhancing the T cell response is sufficient for optimal virus clearance and protection from disease in young BALB/c mice. Dendritic cell (DC) vaccination and transfer of virus-specific T cells into infected BALB/c and immunodeficient mice (SCID-severe combined immunodeficiency) will be used in this aim.
Specific aim 2. To determine if an inefficient T cell response is also the basis for severe disease in aged mice. The goal of this specific aim will be compare the quality and quantity of the T cell response in young and aged B6 mice and determine whether enhancement of the response in aged mice affords protection.
Specific aim 3. To determine the basis of the poor activation of the innate, and ultimately, the T cell response in aged B6 mice. The role of TLR signaling will be investigated in this aim. Previous work in the SARS field has emphasized the importance of the innate immune response in protection. Our results suggest that while the innate response is poorly activated in young and aged mice prone to severe disease, the anti-virus T cell response may be most critical for improved outcomes. At the completion of the proposal, we will better understand the relative importance of the two arms of the immune response in SARS.
Severe Acute Respiratory Syndrome (SARS), caused by a coronavirus, is a useful model for understanding severe respiratory disease caused by pathogens in general, especially in aged populations. This project is based on new information showing a critical role for the anti-virus T cell response in protection from severe disease. Understanding the role of this response is critical for understanding SARS-CoV pathogenesis and in the development of safe and effective SARS-coronavirus vaccines.
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