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.

The SARS coronavirus is a highly pathogenic respiratory virus that caused the first epidemic of the 21 st century. During the epidemic ,10% of those infected died and the elderly were particularly vulnerable. Severe cases developed acute lung injury with pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS). Little is known about the molecular mechanisms governing its virus pathogenesis and high lethality. Using a mouse model of infection with the epidemic strain of SARS-CoV (Urbani) as well as a recombinant mouse adapted strain of SARS-CoV (rMA15), we showed that a protein normally associated with the innate immune response, STAT1, plays an important role in the development of severe end stage lung injury. However, the lack of a normal innate immune type I, type II and type III interferon response did not enhance virus pathogenesis. Our work suggests that STAT1 may play a key role in development of acute lung injury and other chronic lung pathology, most likely by affecting cell proliferation and wound repair pathways.