Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease
| Autor: | William O.C.M. Cookson, Maria-Belen Trujillo-Torralbo, Nicholas Glanville, Patrick Mallia, Phillip James, Elena M. Turek, Aran Singanayagam, Nathan W. Bartlett, Peter Fenwick, Eteri Bakhsoliani, Leah Cuthbertson, Maria Adelaide Calderazzo, Samuel V. Kemp, Lydia J. Finney, Thomas B. Clarke, Michael R. Edwards, Jadwiga A. Wedzicha, Joseph Footitt, Sebastian L. Johnston, Miriam F. Moffatt |
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| Přispěvatelé: | Wellcome Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Receptor expression medicine.medical_treatment Research & Experimental Medicine medicine.disease_cause Cathelicidin Mice Pulmonary Disease Chronic Obstructive 0302 clinical medicine Adrenal Cortex Hormones Lung 11 Medical and Health Sciences GENE-EXPRESSION COPD RECEPTOR EXPRESSION EPITHELIAL-CELLS General Medicine Bacterial Infections 3. Good health medicine.anatomical_structure Streptococcus pneumoniae Medicine Research & Experimental lipids (amino acids peptides and proteins) Female Life Sciences & Biomedicine RHINOVIRUS INFECTION Article 03 medical and health sciences HOST-DEFENSE Immunity Cathelicidins medicine COPD PATIENTS Animals Humans ANTIMICROBIAL PEPTIDE Aged Science & Technology business.industry Cell Biology IN-VITRO 06 Biological Sciences medicine.disease CATHEPSIN-D respiratory tract diseases Pneumonia 030104 developmental biology SALMETEROL/FLUTICASONE PROPIONATE 030228 respiratory system Immunology Dysbiosis Fluticasone business Antimicrobial Cationic Peptides |
| Zdroj: | Sci Transl Med |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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