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 contrast to the results from IFN receptor knockout mice, previous studies have suggested that STAT1 2/2 mice do not clear the Urbani virus by day 22 post-infection [29] . We infected STAT12/2 mice to evaluate whether the absence of a downstream IFN signaling protein results in increased susceptibility to SARS-CoV infection, and to determine the course of infection and pathologic changes associated with the virulent mouse-adapted virus. Importantly, STAT12/2 mice infected with rMA15 virus were more susceptible to disease than 129 WT, IFNAR12/2 or IFNGR2/2 mice. Following rMA15 virus infection, STAT12/2 mice lost 15% of their starting weight by day 4 and continued to lose weight through day 9 post-infection ( Figure 1 ). As weight loss approached 30%, the mice were moribund and succumbed to lethal infection. In stark contrast and consonant with earlier reports, STAT12/2 mice infected with Urbani virus initially gained weight as 129 WT mice did, through day 12 post-infection ( Figure S1 ). However, over the next 15 days they displayed worsening clinical disease and lost significant body weight. They did not recover by day 29 post-infection, and 30% of them died.