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.

In contrast to the existing paradigm, SARS-CoV infection is successfully controlled and cleared in IFNAR12/2, IFNGR2/2, IFNAGR2/2 and IFNLR deficient mice while deletion of STAT1 leads to increased virus replication, morbidity and mortality following infection with either the human epidemic strain of SARS-CoV (Urbani) or a mouse adapted strain (rMA15). These results suggest a novel mechanism of STAT1 regulation of severe end stage lung disease following SARS-CoV infection that is independent of it's roles in IFN signaling and ISG expression. Although it is possible that cooperative combinations of several IFNs (IFNa/b, IFNc, IFNl) that signal through STAT1 are required to regulate SARS-CoV infection, we feel that the possibility exists that STAT1's role in controlling cell proliferation and wound healing may be the base cause of the increased disease seen in STAT12/2 mice. Nevertheless, the development of triple knockouts affecting all 3 IFN receptors would address this mechanistic possibility.