Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation

  • A Corrigendum to this article was published on 01 November 2017

Abstract

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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Figure 1: Host dsDNA is released during human RV infection, is increased in RV-induced asthma exacerbation and is correlated with type-2 cytokine production and exacerbation severity.
Figure 2: RV-induced exacerbation of allergic airway inflammation and type-2 immune responses are associated with host dsDNA release in mice.
Figure 3: DNase treatment prevents RV-induced type-2-mediated exacerbation of allergic airway inflammation.
Figure 4: Host dsDNA is sufficient to exacerbate type-2 immune responses in allergic mice.
Figure 5: DNase treatment inhibits monocyte-derived DC recruitment during RV-induced exacerbation of allergic airway inflammation.
Figure 6: NETs released during RV infection promote type-2-immune-mediated exacerbation of allergic airway inflammation.

Change history

  • 12 July 2017

    In the version of this article initially published, Dr. Nathan W Bartlett was inadvertently omitted from the author list and the Contributions section. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

Author information

M.T. made the initial observation by analyzing human samples, performed most of the experiments and analyzed the data. M.T. designed the experiments with the help of M.R.E., R.S., T.M., F.B., N.W.B. and S.L.J. D.J.J. conducted the human experimental infection study, provided associated data and designed Supplementary Table 1. S.L.J. was the principal investigator for the human experimental-infection study. M.T., D.S. and A.G. performed the western blot experiments. D.S., Y.M.C., N.W.B. and H.M. helped M.T. to process mouse samples in the laboratory. C.R. participated in confocal studies and experiments involving ΔdblGATA BALB/c mice. J.A. grew and purified virus with assistance from N.W.B. F.F. performed human and part of mouse statistical analyses. T.-D.T. and V.P. contributed to experiments and discussion related to NET detection and inhibition. M.T. and T.M. designed the figures. All authors provided feedback on the manuscript; M.T., T.M., F.B. and S.L.J. wrote the manuscript. T.M., F.B. and S.L.J. supervised the project; F.B. and S.L.J. secured funding.

Correspondence to Fabrice Bureau or Thomas Marichal or Sebastian L Johnston.

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Competing interests

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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