Abstract:
: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 cepaciacomplex 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.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Cantin AM,Ouellet C,Cloutier A,McDonald PPdoi
10.3389/fphar.2020.554353subject
Has Abstractpub_date
2020-09-30 00:00:00pages
554353issn
1663-9812journal_volume
11pub_type
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