SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism

Frieman, Matthew B.; Chen, Jun; Morrison, Thomas E.; Whitmore, Alan; Funkhouser, William; Ward, Jerrold M.; Lamirande, Elaine W.; Roberts, Anjeanette; Heise, Mark; Subbarao, Kanta; Baric, Ralph S.

The molecular mechanisms governing SARS-CoV pathogenesis have only recently begun to be evaluated using mice with targeted genetic defects challenged with the rMA15 virus. Sheahan et. al. identified a role for Myd88, an adapter protein of TLR signaling, and RAG1, necessary for antibody production, in protection from infection and disease. Myd88 2/2 mice showed an enhanced susceptibility to rMA15 virus infection in C57/B6 mice [26] and RAG12/2 mice showed no increased morbidity and mortality from rMA15 virus infection, viral replication in the lungs was detectable through 28 days post-infection [26] . These data suggest that an intricate balance between the innate and adaptive immune response is necessary for protection from SARS-CoV infection. We are currently working on understanding how these two processes interact in the host. Using proteomic and microarray analyses Cameron et al [22] showed that individuals who survived SARS-CoV infection had controlled innate immune, ISG and cytokine responses while individuals who progressed to severe disease demonstrated an uncontrolled innate immune response, with high levels of ISG and immunoglobulin expression, increased cytokine responses and poor antibody responses to the spike protein. The cause of this lack of regulation is not understood.