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.

SARS-CoV, like many highly pathogenic viruses, expresses several proteins that antagonize the IFN sensing and amplification network. SARS-CoV ORF6 blocks STAT1 nuclear import [18] , PLP blocks IRF3 activation [51] , NSP7 [51] , NSP15 [51] , ORF3b and N have been shown to be IFN antagonists as well [19] . Importantly, these antagonists only function in the context of SARS-CoV infection within discrete permissive cells. This suggests that in infected cells, the multiple pathways that inhibit IFN signaling may create essentially a STAT2/2 environment which may contribute to the further pathology seen during disease. As has been described with influenza, it is likely that a cytokine storm significantly contributes to increased pathogenic outcomes by targeting non-infected cells. The loss of STAT1 in other cells of the knockout mouse may contribute as we have described here, to loss of wound healing control and induction of fibrosis, leading to the development of the lethal disease state after SARS-CoV infection.