Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

Bart Cortjens*, Onno J. De Boer, Rineke De Jong, A.F.G. Antonis, Yanaika S. Sabogal Piñeros, René Lutter, Job B.M. Van Woensel, Reinout A. Bem

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

58 Citations (Scopus)

Abstract

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction.

Original languageEnglish
Pages (from-to)401-411
JournalThe Journal of Pathology
Volume238
Issue number3
DOIs
Publication statusPublished - 2016

Fingerprint

Respiratory Syncytial Viruses
Virus Diseases
Airway Obstruction
Respiratory Tract Diseases
Lung
Neutrophils
Virion
DNA
Extracellular Traps
Bovine respiratory syncytial virus
Human respiratory syncytial virus
Viral Antigens
Pancreatic Elastase
Bronchoalveolar Lavage Fluid
Mucus
Histones
Peroxidase
Cell Biology

Keywords

  • airway obstruction
  • bronchiolitis
  • inflammation
  • mucus
  • neutrophil extracellular traps
  • pneumovirus

Cite this

Cortjens, B., De Boer, O. J., De Jong, R., Antonis, A. F. G., Sabogal Piñeros, Y. S., Lutter, R., ... Bem, R. A. (2016). Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. The Journal of Pathology, 238(3), 401-411. https://doi.org/10.1002/path.4660
Cortjens, Bart ; De Boer, Onno J. ; De Jong, Rineke ; Antonis, A.F.G. ; Sabogal Piñeros, Yanaika S. ; Lutter, René ; Van Woensel, Job B.M. ; Bem, Reinout A. / Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. In: The Journal of Pathology. 2016 ; Vol. 238, No. 3. pp. 401-411.
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abstract = "Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction.",
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Cortjens, B, De Boer, OJ, De Jong, R, Antonis, AFG, Sabogal Piñeros, YS, Lutter, R, Van Woensel, JBM & Bem, RA 2016, 'Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease', The Journal of Pathology, vol. 238, no. 3, pp. 401-411. https://doi.org/10.1002/path.4660

Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. / Cortjens, Bart; De Boer, Onno J.; De Jong, Rineke; Antonis, A.F.G.; Sabogal Piñeros, Yanaika S.; Lutter, René; Van Woensel, Job B.M.; Bem, Reinout A.

In: The Journal of Pathology, Vol. 238, No. 3, 2016, p. 401-411.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

AU - Cortjens, Bart

AU - De Boer, Onno J.

AU - De Jong, Rineke

AU - Antonis, A.F.G.

AU - Sabogal Piñeros, Yanaika S.

AU - Lutter, René

AU - Van Woensel, Job B.M.

AU - Bem, Reinout A.

PY - 2016

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N2 - Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction.

AB - Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction.

KW - airway obstruction

KW - bronchiolitis

KW - inflammation

KW - mucus

KW - neutrophil extracellular traps

KW - pneumovirus

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DO - 10.1002/path.4660

M3 - Article

VL - 238

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JO - The Journal of Pathology

JF - The Journal of Pathology

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