Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
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The authors thank all the CBS team from Imperial College London for animal management, M. Paulsen of the Flow Cytometry Core Facility from St Mary's Campus (Imperial College London) for giving advice, and C. Tytgat for secretarial assistance. The authors also thank S. Ormenese and J.J. Goval of the Cell Imaging Platform of the Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA, Liège, Belgium) for help with confocal microscopy. M.T. is a postdoctoral fellow who has been supported by the Wallonie-Bruxelles International organization and by the European Academy of Allergy and Clinical Immunology. T.M. is a Research Associate of the F.R.S-FNRS and is supported by the Acteria Foundation. This work was supported by the European Research Council (ERC FP7 grant number 233015) to S.L.J. a Chair from Asthma UK (number CH11SJ) to S.L.J. the Medical Research Council Centre (grant number G1000758); National Institute of Health Research (NIHR) Biomedical Research Centre (grant number P26095); Predicta FP7 Collaborative Project (grant number 260895); and the NIHR Biomedical Research Centre at Imperial College London. S.L.J. is a NIHR Senior Investigator.
D.J.J. has received support for travel expenses to attend Respiratory Conferences from AstraZeneca, Boehringer Ingelheim (UK) and GSK. S.L.J. reports grants and/or personal fees from Centocor; Sanofi Pasteur; GSK; Chiesi; Boehringer Ingelheim; Novartis; grants, personal fees and shareholding from Synairgen; personal fees from Bioforce outside the submitted work; In addition, S.L.J. is involved in patents relating to use of interferon-β and interferon-λ for the treatment and prevention of virally induced exacerbation in asthma and chronic pulmonary obstructive disease, and for the induction of cross-reactive cellular responses against rhinovirus antigens.
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Toussaint, M., Jackson, D., Swieboda, D. et al. Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation. Nat Med 23, 681–691 (2017). https://doi.org/10.1038/nm.4332
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