Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells.
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.
Department of Clinical Research, University of Bern, Bern, Switzerland.
Marjolaine
M
Vareille
Elisabeth
E
Kieninger
Marco P
MP
Alves
Brigitte S
BS
Kopf
Alexander
A
Möller
Thomas
T
Geiser
Sebastian L
SL
Johnston
Michael R
MR
Edwards
Nicolas
N
Regamey
D000208:Acute Disease; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007370:Interferon Type I / Q000276:immunology; D016899:Interferon-beta / Q000172:deficiency / Q000276:immunology* / Q000494:pharmacology; D007372:Interferons / Q000172:deficiency* / Q000276:immunology; D007378:Interleukins / Q000172:deficiency / Q000276:immunology*; D010850:Picornaviridae Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D050199:Podocytes / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology*; D012229:Rhinovirus / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D000095022:Interferon Lambda
D000998:Antiviral Agents; D007370:Interferon Type I; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda