title: RIG-I mediates the co-induction of tumor necrosis factor and type I interferon elicited by myxoma virus in primary human macrophages.
abstract: The sensing of pathogen infection and subsequent triggering of innate immunity are key to controlling zoonotic infections. Myxoma virus (MV) is a cytoplasmic DNA poxvirus that in nature infects only rabbits. Our previous studies have shown that MV infection of primary mouse cells is restricted by virus-induced type I interferon (IFN). However, little is known about the innate sensor(s) involved in activating signaling pathways leading to cellular defense responses in primary human immune cells. Here, we show that the complete restriction of MV infection in the primary human fibroblasts requires both tumor necrosis factor (TNF) and type I IFN. We also demonstrate that MV infection of primary human macrophages (pHMs) activates the cytoplasmic RNA sensor called retinoic acid inducible gene I (RIG-I), which coordinately induces the production of both TNF and type I IFN. Of note, RIG-I sensing of MV infection in pHMs initiates a sustained TNF induction through the sequential involvement of the downstream IFN-regulatory factors 3 and 7 (IRF3 and IRF7). Thus, RIG-I-mediated co-induction of TNF and type I IFN by virus-infected pHMs represents a novel innate defense mechanism to restrict viral infection in human cells. These results also reveal a new regulatory mechanism for TNF induction following viral infection.
authors.affiliation: BioTherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Fuan
authors.initials: F
authors.lastname: Wang
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Gao
authors.forename: John W
authors.initials: JW
authors.lastname: Barrett
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.forename: Eric
authors.initials: E
authors.lastname: Bartee
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mohamed
authors.forename: Masmudur
authors.initials: M
authors.lastname: Rahman
authors.forename: Steve
authors.initials: S
authors.lastname: Werden
authors.forename: Timothy
authors.initials: T
authors.lastname: Irvine
authors.forename: Jingxin
authors.initials: J
authors.lastname: Cao
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dekaban
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
mesh_terms: D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004338:Drug Combinations; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D054884:Host-Pathogen Interactions; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D009233:Myxoma virus / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1