SARS-CoV causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology oftentimes progresses to acute respiratory distress and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and one year old aged mice do not develop severe clinical disease following wildtype SARS-CoV infection, we used the mouse-adapted strain of SARS-CoV (called MA15) that we developed, that was shown to cause lethal infection in these animals. To understand the genetic contributions to increased pathogenesis of MA15 in rodents, in collaboration with scientists at the Universities of North Carolina and Maryland, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral Spike (S) glycoprotein, and to a much less rigorous extent the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse ACE2 receptor not only in MA15, but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to findings in young animals, mutations to revert to the wild-type sequence in NSP9 and the S glycoprotein were not sufficient to significantly attenuate the virus when compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. 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.