Essential Role of mda-5 in Type I IFN Responses to Polyriboinosinic:Polyribocytidylic Acid and Encephalomyocarditis picornavirus

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 22; pp. 8459 - 8464
• Main Authors: Gitlin, Leonid, Barchet, Winfried, Gilfillan, Susan, Cella, Marina, Beutler, Bruce, Flavell, Richard A., Diamond, Michael S., Colonna, Marco
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.05.2006; National Acad Sciences
• Subjects: Animals; Biological Sciences; Bone Marrow Cells - cytology; Bones; Cardiovirus Infections - genetics; Cardiovirus Infections - immunology; Cardiovirus Infections - pathology; Cardiovirus Infections - virology; Cell Differentiation; Cells, Cultured; Cytokines; DEAD-box RNA Helicases; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Susceptibility; Double stranded RNA; Encephalomyocarditis virus; Encephalomyocarditis virus - immunology; Immune system; Infections; Interferon Type I - immunology; Interferon Type I - secretion; Interferon-Induced Helicase, IFIH1; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - secretion; Mice; Mice, Knockout; Picornavirus; Polynucleotides - immunology; Ribonucleic acid; RNA; RNA Helicases - deficiency; RNA Helicases - genetics; RNA Helicases - metabolism; RNA viruses; Rodents; Secretion; Survival Rate; T cell receptors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0603082103

The innate immune system recognizes viral dsRNA through two distinct pathways; the Toll-like receptor 3 (TLR3) pathway detects dsRNA phagocytosed in endosomes; the helicases retinoic acidinduced protein I (RIG-I) and melanoma differentiation-associated gene-5 (mda-5) detect cytoplasmic dsRNA generated during viral replication. Both RIG-I and mda-5 can bind polyriboinosinic:polyribocytidylic acid (polyl:C), the synthetic analog of viral dsRNA, and mediate type I IFN responses to polyl:C and multiple RNA viruses in vitro. We generated mda-5-deficient mice and showed that mda-5 is the dominant receptor mediating type I IFN secretion in response to polyl:C in vitro and in vivo. Moreover, mda-5-/-mice exhibited a selectively impaired antiviral response to encephalomyocarditis picornavirus, indicating functional specialization of mda-5 in vivo.