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.

To understand the role of type I (IFNa/b) and type II IFN (IFNc) in the response to SARS-CoV infection we infected IFN receptor 2/2 mice with either a late phase SARS-CoV (Urbani) virus or a recombinant isogenic mouse-adapted virus (rMA15) that contained six virulence modifying mutations [30] , anticipating that the mouse-adapted virus may display more prominent pathogenicity than the Urbani virus. The Urbani virus and the equivalent recombinant icSARS viruses are not lethal in 10-wk old BALB/c, C57BL6 and 129 WT mice, typically replicating in the lungs with a peak titer at 2 days post-infection (dpi) before being cleared over the next 2-4 days without clinical disease or mortality [26, 30] . In contrast, the rMA15 virus is lethal in 10-wk old BALB/c mice causing greater than 20% weight loss by 4 days post-infection and death by 4-5 days post-infection. We infected 129 WT, Type I IFN receptor knockout mice (IFNAR12/2) and Type I/II double IFN receptor knockout mice (IFNAGR2/2) with the Urbani virus ( Figure S1 ) and 129 WT, IFNAR12/2 and IFNGR2/2 with the rMA15 virus ( Figure 1 ).