Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells
- Marjolaine Vareille1,2,3,4,
- Elisabeth Kieninger1,4,
- Marco P Alves1,4,
- Brigitte S Kopf1,4,
- Alexander Möller5,
- Thomas Geiser6,
- Sebastian L Johnston7,
- Michael R Edwards7,
- Nicolas Regamey1,4
- 1Department of Clinical Research, University of Bern, Bern, Switzerland
- 2Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- 3Laboratoire d'Immunologie, Facultés de Médecine et Pharmacie, Clermont-Ferrand, France
- 4Division of Respiratory Medicine, Department of Paediatrics, Inselspital and University of Bern, Bern, Switzerland
- 5Department of Respiratory Medicine, University Children's Hospital, Zürich, Switzerland
- 6Division of Respiratory Medicine, University Hospital of Bern, Inselspital, Bern, Switzerland
- 7Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity & MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK
- Correspondence to Professor Nicolas Regamey, Division of Respiratory Medicine, Department of Paediatrics, University Children's Hospital of Bern, Inselspital, Bern 3010, Switzerland;
Contributors Conception and design: MV, EK, MRE, NR. Acquisition of data: MV, EK, MPA, BSK, AM, NR. Analysis and interpretation: MV, EK, BSK, SLJ, MRE, NR. Drafting the manuscript for important intellectual content: MV, EK, MPA, BSK, AM, TG, SLJ, MRE, NR. Final approval of the manuscript: all authors.
- Received 28 April 2011
- Accepted 30 November 2011
- Published Online First 2 January 2012
Background Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF.
Methods Early innate immune responses towards rhinoviruses (RV-16, major-type and RV-1B, minor-type) in CF and non-CF bronchial epithelial cell lines and primary nasal and bronchial epithelial cells from patients with CF (n=13) and healthy controls (n=24) were studied.
Results Rhinovirus RNA expression and virus release into supernatants was increased more than tenfold in CF cells compared with controls. CF cells expressed up to 1000 times less interferon (IFN) type I (β) and type III (λ) mRNA and produced less than half of IFN-β and IFN-λ protein compared with controls. In contrast, interleukin 8 production was not impaired, indicating a selective deficiency in the innate antiviral defence system. Deficient IFN production was paralleled by lower expression of IFN-stimulated genes including myxovirus resistance A, 2′,5′-oligoadenylate synthetase, viperin and nitric oxide synthase 2. Addition of exogenous type I and III IFNs, particularly IFN-β, restored antiviral pathways and virus control in CF cells, underscoring the crucial role of these molecules.
Conclusions This study describes a novel mechanism to explain the increased susceptibility of patients with CF to rhinovirus infections. A profound impairment of the antiviral early innate response in CF airway epithelial cells was identified, suggesting a potential use of IFNs in the treatment of rhinovirus-induced CF exacerbations.
- Cystic fibrosis
- airway epithelium
- infection control
- paediatric lung disaese
- innate immunity
- viral infection
- allergic alveolitis
- drug induced lung disease
- interstitial fibrosis
- pulmonary vasculitis
- rare lung diseases
- asthma mechanisms
- bacterial infection
- COPD exacerbations
- cytokine biology
- paediatric asthma
- cytokine biology
- paediatric physician
- respiratory infection
MV and EK contributed equally.
Funding This work was supported by the Swiss National Science Foundation (PP00P3_123453/1) (NR), the ERS/Marie Curie Joint Research Fellowship (short-time fellowship) (MV), the Fondazione Ettore e Valeria Rossi (long-time fellowship) (EK) and the Austrian, German and Swiss Paediatric Respiratory Society (short-time fellowship) (EK).
Competing interests SLJ has received consulting/lecturing fees and/or research grants from AstraZeneca, Centocor, GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur and Synairgen.
Patient consent Obtained.
Ethics approval The study protocol was approved by the ethics committee of the Canton of Bern, Switzerland.
Provenance and peer review Not commissioned; externally peer reviewed.