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 infection in humans rapidly progressed from an atypical pneumonia, to acute phase diffuse alveolar damage and ARDS during the first 10 days of acute lung injury. In many patients this is followed by the development of an organizing phase DAD after virus clearance. Both pathologies were associated with severe clinical outcomes and death, especially prominent in the elderly. The molecular mechanisms and virus-host signaling networks that regulate these progressive end stage lung diseases are unknown but are of considerable importance, given the global disease burden associated with them. Previous studies in our laboratory have demonstrated that aged mice infected with recombinant viruses encoding S glycoproteins from early phase or zoonotic SARS-CoV strains developed ARDS, characterized by hyaline membranes and DAD. In this report, we show that STAT1 deficient mice are especially prone to the development of organizing phase DAD. The innate immune system plays a central role in regulating early host responses to virus infection and promoting adaptive immune responses. The Type I, II and III IFNs are typically produced by different cell populations and use distinct membrane bound receptors to gain entry into cells; Type I uses IFNAR1, Type II uses IFNGR and Type III uses IL28Ra/IL10Rb. However, all three share a common cytoplasmic signaling protein, called STAT1, that is translocated to the nucleus and induces expression of multiple, overlapping IFN regulated genes (ISGs) [38] . Deletion of any or all of the signaling components involved in the STAT1 signaling pathway diminishes the innate immune response to pathogens and increases susceptibility to several bacterial and viral agents. Mice lacking IFN receptors show increased susceptibility to West Nile [9] , influenza [12, 39] , Ebola [11] , Friend virus [40] , RSV [7, 8] and Poliovirus [41] (reviewed in [42] ). Moreover, the same phenotypes are noted in STAT1 2/2 mice, demonstrating a key role of the entire innate immune pathway in regulating disease severity, viral titers, and pathology [10] . In stark contrast, we demonstrate the paradoxical finding that SARS-CoV Urbani and rMA15 viruses induce severe end stage lung disease by a STAT1 dependent mechanism that is independent of IFN receptor type I, II and III signaling. The data point to a novel mechanism by which STAT1 function regulates disease severity in the lung following SARS-CoV induced acute lung injury.