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 STAT12/2 mice infected with the Urbani virus, there was a similar distribution of bronchial and bronchiolar lesions in the lung as seen in the 129 WT mice at day 3, but with more necrosis and inflammation. Edema was observed around peribronchiolar blood vessels and the larger inflammatory cell infiltrate contained many lymphocytes, and neutrophils with a few eosinophils and macrophages. Abundant viral antigen was seen in bronchiolar epithelium (data not shown). By day 5, the bronchiolar epithelium had foci of regeneration with little necrosis and the peribronchiolar and perivascular inflammation was less severe than at day 3. Plugs of cellular debris and fibrin filled some bronchioles. A blue tinge was noted in the perivascular edema fluid, suggesting early collagen deposition. Viral antigen was much less common in the epithelium but was abundant in the cellular debris in the airways. At day 9, inflammatory cells increased around residual inflammatory lesions, with abundant neutrophils and more macrophages in the lesions. Marked epithelial hyperplasia was also seen in these foci. Bronchiolitis obliterans was seen in a few airways and interstitial lesions developed around some airway lesions, one of which extended to the pleura and producing focal pleuritis. Much of the lung parenchyma was, however, histologically normal. Only a few cells or cell debris was seen expressing viral antigen. By day 15, a fibrinous pleuritis with pyogranulomatous lesions developed in 2 of 3 mice, with focal resolving parenchymal lesions including a few foci of chronic interstitial pneumonia but most of the lung parenchyma remained fairly normal. From day 15-24, a fibrinous peritonitis ( Figure S2A ), pleuritis and pyogranulomatous lesions in spleen, liver and omentum developed as the major lesions that likely contributed to illness and death in the STAT12/2 mice ( Figure S2B -F). These lesions were characterized by a central area of necrosis with numerous neutrophils and an outer zone of macrophages. Viral antigen was found in some of the macrophages in these pyogranulomatous lesions ( Figure S2D , E). Plasma cells became abundant in the splenic lesions by day 24 ( Figure S2G ). Abundant fibrosis (detected by Masson's trichrome stain) was seen in the splenic and liver lesions at day 24 ( Figure S2F ). The lungs of mice from days 15-24 were mostly normal with areas of residual chronic inflammation and a few pyogranulomas, some of which contained viral antigen. The pleura had nodules of pyogranulomatous and fibrinous inflammation.