Abstract
Highly pathogenic avian influenza H5N1 viruses cause severe disease in humans, and dysregulation of cytokine responses is believed to contribute to the pathogenesis of human H5N1 disease. However, mechanisms leading to the increased induction of proinflammatory cytokines by H5N1 viruses are poorly understood. We show that the innate sensing receptor RIG-I is involved in interferon regulatory factor 3 (IRF3), NF-κB nuclear translocation, p38 activation, and the subsequent interferon (IFN) β, IFN-λ1, and tumor necrosis factor α induction during H5N1 infection. Soluble mediators from H5N1-infected human macrophages upregulate RIG-I, MDA5, and TLR3 to much higher levels than those from seasonal H1N1 in uninfected human macrophages and alveolar epithelial cells via paracrine IFNAR1/JAK but not IFN-λ receptor signaling. Compared with H1N1 virus-induced mediators, H5N1 mediators markedly enhance the cytokine response to PolyIC and to both seasonal and H5N1 virus infection in a RIG-I-dependent manner. Thus, sensitizing neighboring cells by upregulation of RIG-I contributes to the amplified cytokine cascades during H5N1 infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism*
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Cells, Cultured
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Cytokines / metabolism*
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DEAD Box Protein 58
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism*
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Humans
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Immunity, Innate
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Influenza A Virus, H1N1 Subtype / genetics
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Influenza A Virus, H1N1 Subtype / immunology
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Influenza A Virus, H5N1 Subtype / genetics
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Influenza A Virus, H5N1 Subtype / immunology*
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Influenza, Human / immunology
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Influenza, Human / metabolism*
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Influenza, Human / virology
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Interferon Regulatory Factor-3 / metabolism
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Interferon-Induced Helicase, IFIH1
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Janus Kinases / immunology
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Macrophages / immunology
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Macrophages / metabolism*
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NF-kappa B / metabolism
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Paracrine Communication / immunology*
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Pulmonary Alveoli / immunology
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Pulmonary Alveoli / metabolism
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RNA, Small Interfering / genetics
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RNA, Viral / metabolism
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Receptor, Interferon alpha-beta / immunology
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Receptors, Immunologic
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Signal Transduction*
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Toll-Like Receptor 3 / metabolism
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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Interferon Regulatory Factor-3
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MAVS protein, human
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NF-kappa B
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RNA, Small Interfering
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RNA, Viral
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Receptors, Immunologic
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Toll-Like Receptor 3
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Receptor, Interferon alpha-beta
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Janus Kinases
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p38 Mitogen-Activated Protein Kinases
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RIGI protein, human
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IFIH1 protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1