Cargando…

Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils

Neutrophil killing of bacteria is mediated by oxidative and non-oxidative mechanisms. Oxidants are generated through the NADPH oxidase complex, whereas antimicrobial proteins and peptides rank amongst non-oxidative host defenses. Mucus hypersecretion, deficient hydration and poor clearance from the...

Descripción completa

Detalles Bibliográficos
Autores principales: Cantin, André M., Ouellet, Cristine, Cloutier, Alexandre, McDonald, Patrick P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554606/
https://www.ncbi.nlm.nih.gov/pubmed/33101020
http://dx.doi.org/10.3389/fphar.2020.554353
_version_ 1783593814255992832
author Cantin, André M.
Ouellet, Cristine
Cloutier, Alexandre
McDonald, Patrick P.
author_facet Cantin, André M.
Ouellet, Cristine
Cloutier, Alexandre
McDonald, Patrick P.
author_sort Cantin, André M.
collection PubMed
description Neutrophil killing of bacteria is mediated by oxidative and non-oxidative mechanisms. Oxidants are generated through the NADPH oxidase complex, whereas antimicrobial proteins and peptides rank amongst non-oxidative host defenses. Mucus hypersecretion, deficient hydration and poor clearance from the airways are prominent features of cystic fibrosis (CF) lung disease. CF airways are commonly infected by Pseudomonas aeruginosa and Burkholderia cepacia complex bacteria. Whereas the former bacterium is highly sensitive to non-oxidative killing, the latter is only killed if the oxidative burst is intact. Despite an abundance of neutrophils, both pathogens thrive in CF airway secretions. In this study, we report that secreted mucins protect these CF pathogens against host defenses. Mucins were purified from CF sputum and from the saliva of healthy volunteers. Whereas mucins did not alter the phagocytosis of Pseudomonas aeruginosa and Burkholderia cenocepacia by neutrophils, they completely suppressed bacterial killing. Accordingly, mucins markedly inhibited non-oxidative bacterial killing by neutrophil granule extracts, or by lysozyme and the cationic peptide, human β defensin-2 (HBD2). Mucins also suppressed the neutrophil oxidative burst through a charge-dependent mechanism that could be reversed by the cationic aminoglycoside, tobramycin. Our data indicate that airway mucins protect Gram-negative bacteria against neutrophil killing by suppressing the oxidative burst and inhibiting the bactericidal capacity of cationic proteins and peptides. Mucin hypersecretion, dehydration, stasis and anionic charge represent key therapeutic targets for improving host defenses and airway inflammation in CF and other muco-secretory airway diseases.
format Online
Article
Text
id pubmed-7554606
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-75546062020-10-22 Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils Cantin, André M. Ouellet, Cristine Cloutier, Alexandre McDonald, Patrick P. Front Pharmacol Pharmacology Neutrophil killing of bacteria is mediated by oxidative and non-oxidative mechanisms. Oxidants are generated through the NADPH oxidase complex, whereas antimicrobial proteins and peptides rank amongst non-oxidative host defenses. Mucus hypersecretion, deficient hydration and poor clearance from the airways are prominent features of cystic fibrosis (CF) lung disease. CF airways are commonly infected by Pseudomonas aeruginosa and Burkholderia cepacia complex bacteria. Whereas the former bacterium is highly sensitive to non-oxidative killing, the latter is only killed if the oxidative burst is intact. Despite an abundance of neutrophils, both pathogens thrive in CF airway secretions. In this study, we report that secreted mucins protect these CF pathogens against host defenses. Mucins were purified from CF sputum and from the saliva of healthy volunteers. Whereas mucins did not alter the phagocytosis of Pseudomonas aeruginosa and Burkholderia cenocepacia by neutrophils, they completely suppressed bacterial killing. Accordingly, mucins markedly inhibited non-oxidative bacterial killing by neutrophil granule extracts, or by lysozyme and the cationic peptide, human β defensin-2 (HBD2). Mucins also suppressed the neutrophil oxidative burst through a charge-dependent mechanism that could be reversed by the cationic aminoglycoside, tobramycin. Our data indicate that airway mucins protect Gram-negative bacteria against neutrophil killing by suppressing the oxidative burst and inhibiting the bactericidal capacity of cationic proteins and peptides. Mucin hypersecretion, dehydration, stasis and anionic charge represent key therapeutic targets for improving host defenses and airway inflammation in CF and other muco-secretory airway diseases. Frontiers Media S.A. 2020-09-30 /pmc/articles/PMC7554606/ /pubmed/33101020 http://dx.doi.org/10.3389/fphar.2020.554353 Text en Copyright © 2020 Cantin, Ouellet, Cloutier and McDonald http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cantin, André M.
Ouellet, Cristine
Cloutier, Alexandre
McDonald, Patrick P.
Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title_full Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title_fullStr Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title_full_unstemmed Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title_short Airway Mucins Inhibit Oxidative and Non-Oxidative Bacterial Killing by Human Neutrophils
title_sort airway mucins inhibit oxidative and non-oxidative bacterial killing by human neutrophils
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554606/
https://www.ncbi.nlm.nih.gov/pubmed/33101020
http://dx.doi.org/10.3389/fphar.2020.554353
work_keys_str_mv AT cantinandrem airwaymucinsinhibitoxidativeandnonoxidativebacterialkillingbyhumanneutrophils
AT ouelletcristine airwaymucinsinhibitoxidativeandnonoxidativebacterialkillingbyhumanneutrophils
AT cloutieralexandre airwaymucinsinhibitoxidativeandnonoxidativebacterialkillingbyhumanneutrophils
AT mcdonaldpatrickp airwaymucinsinhibitoxidativeandnonoxidativebacterialkillingbyhumanneutrophils