title: Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock.
abstract: Chikungunya virus (CHIKV) infections can produce severe disease and mortality. 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-α/β) in serum, ∼50- and ∼10-fold increases in levels of IFN-γ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-α/β receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7(-/-) mice; all but the latter two stained positive in wild-type mice. Vaccination 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-α/β induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-α/β responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome.
authors: Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors: Penny A
authors: PA
authors: Rudd
authors: Jane
authors: J
authors: Wilson
authors: Joy
authors: J
authors: Gardner
authors: Thibaut
authors: T
authors: Larcher
authors: Candice
authors: C
authors: Babarit
authors: Thuy T
authors: TT
authors: Le
authors: Itaru
authors: I
authors: Anraku
authors: Yutaro
authors: Y
authors: Kumagai
authors: Yueh-Ming
authors: YM
authors: Loo
authors: Michael
authors: M
authors: Gale
authors: Shizuo
authors: S
authors: Akira
authors: Alexander A
authors: AA
authors: Khromykh
authors: Andreas
authors: A
authors: Suhrbier
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018354:Alphavirus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000494:pharmacology; D016899:Interferon-beta / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000517:prevention & control; D014779:Virus Replication / Q000187:drug effects
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse