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.

At day 2 post-infection with rMA15 virus, lung lesions in STAT12/2 mice were indistinguishable from those seen in 129 WT, IFNAR12/2 and IFNGR2/2 infected animals. By day 5 post-infection, lung lesions were more severe in STAT12/2 mice, consistent with persistently high virus titers ( Figure 2 ). Two features were notable; first, the extent of inflammation was more severe in STAT12/2 mice, with a much greater number of macrophages infiltrating into all areas of the lung, a finding that was not seen in the other mouse strains. Second, thickening of the alveolar septa was seen throughout the lungs with perivascular and peribronchial thickening. By 9 days post-infection, the inflammation continued to increase in STAT12/2 mice while lung inflammation was subsiding in 129 WT, IFNAR12/2 and IFNGR2/2 infected mice. In STAT12/2 mice, inflammation was pervasive throughout the lungs with densely packed infiltrating cells especially prominent throughout the periphery of the tissue. Macrophages continued to infiltrate with the majority residing in the alveolar interstitium. Interestingly, large foci containing densely packed fibroblasts, macrophages and lymphocytes were seen throughout the lungs and scattered atypical large cells were found throughout the foci. A focal mixed inflammatory infiltrate was found with extensive fibrin deposition. Pleuritis signified by a breakdown of the pleura was seen in most samples as well. This pathology was consistent with proliferative and organizing phase diffuse alveolar damage (DAD). It is noteworthy that similar pathologic lesions were seen in many fatal SARS cases [31] [32] [33] [34] .