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.

STAT1 functions a key gatekeeper in mediating IFNa/b, IFNc and IFNl signaling into the nucleus to induce overlapping but distinct ISGs. Less well appreciated in viral pathogenesis studies, STAT1 also plays key roles in cell cycle arrest and cell proliferation [43] [44] [45] . Thus, STAT1 defects may augment viral lung disease by several potential mechanisms. STAT1 was shown to be an important controller of tumor formation in several types of cancers including lung, colon, pancreatic and brain cancers [46] [47] [48] and its role in cell proliferation has been studied in the context of pulmonary fibrosis [43] . STAT12/2 mouse fibroblasts showed increased proliferation when exposed to growth factors compared to WT mouse fibroblasts. Additionally, STAT12/2 mice demonstrated a greater susceptibility to chemically induced pulmonary fibrosis via bleomycin treatment. These data suggested that outside of the innate immune response, STAT1 may function as a key regulator of cell proliferation and of the wound healing response [49] . Our data also suggest that STAT1 may regulate the wound healing response following acute lung injury associated with viral infection, similar to its cell cycle regulation seen in other models of disease.