title: RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium.
abstract: Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ∼500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-β production, and investigated the importance of IFN-β production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-β through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I-like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-β and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-β production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.
authors.affiliation: Laboratory of Mucosal Immunology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alexis H
authors.initials: AH
authors.lastname: Broquet
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Christopher S
authors.initials: CS
authors.lastname: McAllister
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kagnoff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis* / Q000502:physiology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D020365:RNA Helicases / Q000235:genetics / Q000502:physiology; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D020218:Response Elements / Q000276:immunology; D012401:Rotavirus / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology; D000097905:Roundabout Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020365:RNA Helicases; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C520569:DHX58 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human; C510592:Ifih1 protein, mouse