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Journal of Virology, January 2008, p. 335-345, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01080-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity

Departments of Immunology,¹ Microbiology,² Washington National Primate Research Center, University of Washington, Seattle, Washington,³ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas,⁴ Departments of Microbiology,⁵ Medicine,⁶ Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York,⁷ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan⁸

Received 18 May 2007/ Accepted 4 October 2007

Alpha/beta interferon immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We directly compared the innate immune signaling requirements of representative viruses of the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Reoviridae for RIG-I, MDA5, and interferon promoter-stimulating factor 1 (IPS-1). In cultured fibroblasts, IPS-1 was essential for innate immune signaling of downstream interferon regulatory factor 3 activation and interferon-stimulated gene expression, but the requirements for RIG-I and MDA5 were variable. Each was individually dispensable for signaling triggered by reovirus and dengue virus, whereas RIG-I was essential for signaling by influenza A virus, influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified cellular genes triggered during influenza A virus infection whose expression was strictly dependent on RIG-I and which are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation associated with the host response to contemporary and pandemic strains of influenza virus. These results define IPS-1-dependent signaling as an essential feature of host immunity to RNA virus infection. Our observations further demonstrate differential and redundant roles for RIG-I and MDA5 in pathogen recognition and innate immune signaling that may reflect unique and shared biologic properties of RNA viruses whose differential triggering and control of gene expression may impact pathogenesis and infection.

Published ahead of print on 17 October 2007.

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