Interferon Response Factors 3 and 7 Protect against

Chikungunya virus (CHIKV) infections can produce severe disease andmortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7/) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-/) in serum,50- and10-fold increases in levels of IFN- and tumor necrosis factor (TNF), re-spectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytope-nia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-/ receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononu-clear cells, chondrocytes, and keratinocytes in IRF3/7/mice; all but the latter two stained positive in wild-type mice. Vaccina-tion protected IRF3/7/mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1- and TRIF-dependent pathways were primarily responsible for IFN-/ induction, with IRF7 being upregulated>100-fold in in-fected wild-type mice. These studies suggest that inadequate IFN-/ responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemor-rhagic fever/dengue shock syndrome. Chikungunya virus (CHIKV) is a mosquito-borne, single-stranded, positive-sense RNA virus (genus Alphavirus) tha