• Open Access

Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus

Authors

  • Nathan W. Bartlett,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Louise Slater,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Nicholas Glanville,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Jennifer J. Haas,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Gaetano Caramori,

    1. Sezione di Malattie dell'Apparato Respiratorio, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (CEMICEF), University of Ferrara, Ferrara, Italy
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  • Paolo Casolari,

    1. Sezione di Malattie dell'Apparato Respiratorio, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (CEMICEF), University of Ferrara, Ferrara, Italy
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  • Deborah L. Clarke,

    1. Centre for Respiratory Infections, Imperial College London, London, UK
    2. Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK
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  • Simon D. Message,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
    4. Imperial College Healthcare National Health Service Trust, London, UK
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  • Julia Aniscenko,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Tatiana Kebadze,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Jie Zhu,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
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  • Patrick Mallia,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
    4. Imperial College Healthcare National Health Service Trust, London, UK
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  • Joseph P. Mizgerd,

    1. The Pulmonary Centre, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Maria Belvisi,

    1. Centre for Respiratory Infections, Imperial College London, London, UK
    2. Respiratory Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK
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  • Alberto Papi,

    1. Sezione di Malattie dell'Apparato Respiratorio, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell'Apparato Respiratorio (CEMICEF), University of Ferrara, Ferrara, Italy
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  • Sergei V. Kotenko,

    1. Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, UMDNJ-New Jersey Medical School, Newark, NJ, USA
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  • Sebastian L. Johnston,

    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
    4. Imperial College Healthcare National Health Service Trust, London, UK
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  • Michael R. Edwards

    Corresponding author
    1. Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK
    2. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
    3. Centre for Respiratory Infections, Imperial College London, London, UK
    • Tel: +44 0 20 7594 3775; Fax: +44 0 20 7262 8913
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Abstract

The importance of NF-κB activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-κB p65 nuclear expression, NF-κB p65 DNA binding in lung tissue and NF-κB-regulated airway inflammation. In vitro inhibition of NF-κB reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-κB p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1−/− mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-κB p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases.

See accompanying article http://dx.doi.org/10.1002/emmm.201202032

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