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.

STAT1 is a mediator of Type III IFN (IFN L, Lambda) signaling in addition to Type I and II IFN signaling. IFNL is minimally but significantly upregulated during infection in WT 129 mice at day 2 post infection which decreases through the course of 9 days post infection ( Figure 5A ). The receptor for IFNL is a heterodimer of IL10Rb and IL28Ra. IL28Ra2/2 mice have been generated on the BALB/c mouse background but not on the 129 WT mouse background. Thus, although direct comparison with the other mouse strains is not possible, experiments with SARS-CoV in these mice are still informative. As in the C57B6 background, the Urbani virus does not cause disease or weight loss but the virus replicates in the lungs of BALB/c mice. Virus reaches peak titer by day 2 post-infection and infection is resolved by day 7 [36] . In contrast, rMA15 virus infection of BALB/c mice causes death by day 4 or 5 post-infection [30] . We hypothesized that if IFNL was important for protection from SARS-CoV infection, the virus would be more virulent in mice lacking the IFNL receptor and IFNL receptor knockout mice would show evidence of disease while normal BALB/c mice would not. Further, rMA15 virus infection of IL28Ra2/2 mice may result in enhanced pathology with more weight loss, higher virus titer, or increased lung pathology.