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

• Published in: Frontiers in pharmacology Vol. 11; p. 554353
• Main Authors: Cantin, André M, Ouellet, Cristine, Cloutier, Alexandre, McDonald, Patrick P
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30-09-2020
• Subjects: Burkholderia cepacia; cationic peptides; cystic fibrosis; NADH oxidase; NADPH oxidase; Pharmacology; Pseudomonas aeruginosa; Pseudomonas aeruginosa; cationic peptides; Burkholderia cepacia; NADPH oxidase; cystic fibrosis; NADH oxidase
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.554353

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
and
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
and
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.