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 this paper, we compare the pathogenesis of both the epidemic virus (Urbani) and an isogenic, highly pathogenic mouseadapted SARS-CoV (rMA15) in different mouse strains, each deficient in different innate immune signaling components. Specifically, we tested the role of type I, type II, and type III IFN and STAT1 in protection from SARS-CoV infection. We have found that absence of the IFN a/b, IFNc and IFNl, receptors alone or in some instances together, had a limited impact on pathogenicity and clearance of the non-lethal and lethal strains of SARS-CoV in mice. However, STAT1 deficient mice show increased susceptibility, prolonged virus shedding and mortality following infection with either virus. Importantly, STAT12/2 animals developed an organizing phase DAD, similar to lesions noted in severe late stage human cases of SARS. Our data reveals a new mechanistic pathway by which STAT1 regulates the severity of viral pathogenesis in the lung. We show that SARS-CoV pathogenesis is STAT1 dependent but independent of type I, II and III IFN signaling, and we provide evidence consistent with an essential role for STAT1 in the control of SARS-CoV replication, cell proliferation, wound repair and progression to severe organizing phase DAD and lethal disease.