We characterized the cellular immune response to SARS-CoV infection in 12-14 month old BALB/c mice. Following intranasal administration, the virus replicated in the lungs with peak titers on day 2 post-infection. Enhanced production of proinflammatory cytokines (TNF-a, IL-6) and chemokines (CXCL10, CCL2, CCL3, CCL5) correlated with migration and activation of NK cells, macrophages (MΦ) and plasmacytoid DC (pDCs) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of pro- and inflammatory cytokines (TNF-a, IL-6, IFN-g, IL-2, IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, CCL5) and receptors (CXCR3, CCR2, CCR5), was detected in the lungs, associated with an influx and activation of T lymphocytes. An increase of CD4+CD25+Foxp3+ regulatory T cells and activated/effector CD4+ T cells was found on day 7 in the lungs. Our findings allow new insights into the cellular immune responses to SARS-CoV infection in the senescent mouse model that suggest that T cell immunity may contribute to viral clearance and pneumonitis in primary SARS-CoV lung infection. The role of T cells in the pathogenesis and clearance of SARS-CoV was also evaluated in 1214 month old BALB/c mice. Depletion of CD8+ T cells at the time of infection did not affect viral replication or clearance but depletion of CD4+ T cells resulted in delayed clearance of SARS-CoV from the lungs and was associated with an enhanced immune-mediated interstitial pneumonitis. CD4+ T cell depletion resulted in reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of inflammatory cells. Viral clearance in the absence of both CD4+ and CD8+ T cells and antibodies was associated with an innate immune response. Our findings provide new insights into the role of CD4+ but not CD8+ T cells in primary SARS-CoV infection in this model. The goal of our SARS program was driven by the public health need in 2003 for animal models for the evaluation of vaccines and immunoprophylaxis strategies. We developed mouse, hamster and non-human primate models and collaborated with several scientists from academic institutions and pharmaceutical companies to evaluate the efficacy of candidate vaccines. We have also investigated the pathogenesis of disease in the murine models of SARS. However, since SARS has not reappeared in epidemic form and pandemic influenza is a more imminent threat, we have discontinued active research in SARS and have re-directed the resources to work on pandemic influenza vaccines.
