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Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease

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Title: Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease
Authors: Singanayagam, A
Glanville, N
Cuthbertson, L
Bartlett, NW
Finney, LJ
Turek, E
Bakhsoliani, E
Calderazzo, MA
Trujillo-Torralbo, M-B
Footitt, J
James, PL
Fenwick, P
Kemp, SV
Clarke, TB
Wedzicha, JA
Edwards, MR
Moffatt, M
Cookson, WO
Mallia, P
Johnston, SL
Item Type: Journal Article
Abstract: Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
Issue Date: 28-Aug-2019
Date of Acceptance: 23-Jul-2019
URI: http://hdl.handle.net/10044/1/74112
DOI: https://dx.doi.org/10.1126/scitranslmed.aav3879
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Start Page: 1
End Page: 13
Journal / Book Title: Science Translational Medicine
Volume: 11
Issue: 507
Copyright Statement: © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 107660/Z/15/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
ANTIMICROBIAL PEPTIDE
COPD PATIENTS
CATHEPSIN-D
SALMETEROL/FLUTICASONE PROPIONATE
RHINOVIRUS INFECTION
RECEPTOR EXPRESSION
EPITHELIAL-CELLS
GENE-EXPRESSION
HOST-DEFENSE
IN-VITRO
11 Medical and Health Sciences
06 Biological Sciences
Publication Status: Published
Conference Place: United States
Online Publication Date: 2019-08-28
Appears in Collections:National Heart and Lung Institute
Airway Disease



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