Abstract
Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.
Highlights
Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
We studied the relationship between local bacterial clearance and Airway Surface Liquid (ASL) pH in WT and F508del homozygous human bronchial epithelial cells, with a specific emphasis on physiologically relevant HCO3− and protons (H+) transporters
Results pH is abnormally low in the ASL of CF bronchial epithelial cells
Summary
Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. An abnormally low ASL pH might alter local antibacterial defense by impairing mucin hydration and solubilization, resulting in hyper-viscous mucus, which impedes mucociliary clearance[9,10,11] It reduces the activity of antimicrobial peptides by modulating their native charges[1,5,12,13,14,15]. We studied the relationship between local bacterial clearance and ASL pH in WT and F508del homozygous human bronchial epithelial cells, with a specific emphasis on physiologically relevant HCO3− and protons (H+) transporters
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