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.

IFNc and MCP1 gene expression levels were similar in rMA15 virus-infected 129 WT, IFNAR12/2 and IFNGR-/mice. Transcript levels were induced by day 2 and then decreased through day 9. While STAT12/2 infected mice showed a similar trend of increased transcript levels at day 2, expression levels of IFNc and MCP1 continued to increase through day 9 postinfection. Finally, IL6 expression showed similar kinetics in rMA15 virus infected 129 WT control and IFNAR12/2 mice with peaks at day 2 that decreased to baseline levels by day 5. IFNGR2/2 mice showed similar kinetics, but with lower expression levels at day 2. Comparatively, induction of IL6 in STAT12/2 mice followed a different pattern, with high levels of expression at day 2 post-infection and persistent high level expression through day 9. IFNb, IFNa4, IL28B, IL18, IRF1 and OAS1 were analyzed by Real-time PCR from lung RNA isolated during the rMA15 timecourse in WT, IFNAR2/2 and STAT12/2 mice ( Figure S3) . IFNb, IFNa4, IL28B, IRF1 and OAS1 show a peek of induction at 2dpi for all 3 strains with a reduction throughout the timecouse with a few exceptions. IFNb, IFNa4 and OAS1 show either a sustained or late burst in expression of each in only the STAT12/2 mice. Interestingly, IL18 shows minimal induction (,1.5 fold) in WT mice but even less in the IFNAR2/2 and STAT12/2 mice. Thus, significant differences in cytokine expression patterns were noted between STAT1, WT and IFNAR deficient animals, where typically WT and IFNAR2/2 mice had the same expression patters while STAT12/2 mice were typified by perceived loss of regulatory control and persistent high level expression.