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The Severe Acute Respiratory Syndrome (SARS), caused by a novel coronavirus, SARS-CoV, resulted in substantial morbidity and mortality in 2002-2003. With the lack of SARS recurrence, research efforts to understand pathogenesis and develop effective vaccines and anti-viral therapies have largely halted. However, severe CoV-mediated disease may recur because SARS-like CoVs are present in bat populations and pathogeneic CoVs may arise from widely circulating temperate CoV strains, as has been documented in domesticated animals. Thus, we believe that continued efforts are needed. In this PPG, investigators with experience in coronavirus pathogenesis, molecular biology, immunology and vaccinology will work together to understand how dysregulated innate and adaptive immune responses contribute to SARS disease and will use this information to develop effective SARS-CoV vaccines and anti-viral therapies. Project 1 is based on published and preliminary data showing that the anti-virus T cell response is deficient in mice with severe disease and that correction of this deficit improves survival. Project 2 investigates how SARS-CoV interactions with hACE2, the host cell receptor, results in immune perturbation while the S protein from another coronavirus, HCoV-NL63 which uses the same receptor but causes mild disease, does not. Project 3 investigates how SARS-CoV infection perturbs the renin-angiotensin system via ACE2 signaling, contributing to immune dysregulation and severe disease. Project 4 is based on published data showing that a recombinant SARS-CoV deleted in E protein is a safe and effective vaccine candidate. Second generation vaccine candidates with improved safety and efficacy will be developed, utilizing new information obtained by the other projects.
Project 1: To determine if enhancing the T cell response is sufficient for optimal virus clearance and protection from disease in young BALB/c mice. To determine if an inefficient T cell response is also the basis for severe disease in aged mice. To determine the basis of the poor activation of the innate, and ultimately, the T cell response in aged mice.
Project 2: To dissect the entry pathways used by SARS and NL63-CoVs. To relate virus entry events to proinflammatory cytokine responses. To determine S protein contributions to SARS and NL63-CoV growth and pathogenicity.
Project 3: To determine how airway epithelial cell ACE2 expression is affected by SARS-CoV infection. To characterize the physiologic function of airway epithelial ACE2 during SARS-CoV infection. To identify enzyme activity-independent ACE2 functions that modulate host defense responses.
Project 4: To optimize the immunogenicity of rSARS-CoV-ΔE virus by mutating rather than deleting the E protein. To test rSARS-CoV-E* as vaccine candidates. To increase the safety and titer of selected rSARS-CoV-E* vaccine candidates.
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