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.

Given the importance of the IFN system in regulating virus growth, many highly pathogenic viruses encode proteins that antagonize components of the innate immune system. The Ebola virus encodes VP35 which blocks STAT1 signaling [13, 14] , influenza NS1 blocks IRF3 activation [15, 16] and V proteins from the Nipah and Hendra viruses induce STAT1 degradation [17] . Several IFN antagonist genes are encoded in the SARS-CoV genome and target IFN sensing and signaling and NFKB induction [18] [19] [20] [21] . However, the role of IFN in regulating SARS-CoV pathogenesis in vivo is less clear. From microarray studies using RNA from PBMC's for 50 SARS patients, Cameron et. al. observed a robust type I IFN response early in the disease and predicted that it was essential for viral clearance and clinical recovery [22] . In addition to a strong IFN response, genes such as CCL2 (MCP-1) and CXCL10 (IP-10) that are typically induced by IFN were also up-regulated in patients at early times in SARS-CoV disease. Interestingly, Cameron and colleagues suggested that the IFN response that served to protect recovered SARS patients could become a dysregulated cytokine storm in severe cases and contribute to increased disease and a suboptimal adaptive immune response. The innate immune response to SARS-CoV also changes with age of the host; 12 month old BALB/c mice respond to SARS-CoV with an exacerbated and faster innate immune induction than 6 to 8 week old mice, potentially explaining their increased susceptibility and lung pathology following infection [23, 24] .