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 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.
Highlights
Cystic fibrosis (CF) is a fatal autosomal recessive disease that limits to 50 years or less the median age of patients’ survival (Elborn, 2016)
Despite their markedly different susceptibilities to non-oxidative killing, the growth of both B. cenocepacia and P. aeruginosa was readily counteracted by neutrophils; in the presence of CFAM, bacterial killing of either strain by neutrophils was strongly inhibited (Figures 1C, D)
Phagocytosis of opsonized P. aeruginosa incubated with CFAM was robust at 37°C but was decreased 8-fold at 4°C (Figure 2C), indicating that the bacteria observed at 37°C had been ingested by the neutrophils
Summary
Cystic fibrosis (CF) is a fatal autosomal recessive disease that limits to 50 years or less the median age of patients’ survival (Elborn, 2016). Almost all of the mortality associated with CF stems from respiratory insufficiency accompanied by repeated airway infections (Lund-Palau et al, 2016). Airway infections with Pseudomonas aeruginosa and infectious respiratory exacerbations (Waters et al, 2012) predict poor lung health and mortality in children and adults with CF (Emerson et al, 2002). The lack of functional cystic fibrosis transmembrane conductance regulator protein (CFTR) is associated with deficient cAMP-dependent chloride secretion into the CF airway lumen (Boucher, 2007). Airway mucus is dehydrated, mucins are concentrated and mucociliary clearance is deficient (Perez-Vilar and Boucher, 2004). Persistent bronchopulmonary infections ensue, leading to tissue destruction and respiratory insufficiency (Bergeron and Cantin, 2019)
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