Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

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...

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Bibliographic Details
Published in:Scientific reports Vol. 9; no. 1; p. 6516
Main Authors: Simonin, Juliette, Bille, Emmanuelle, Crambert, Gilles, Noel, Sabrina, Dreano, Elise, Edwards, Aurélie, Hatton, Aurélie, Pranke, Iwona, Villeret, Bérengère, Cottart, Charles-Henry, Vrel, Jean-Patrick, Urbach, Valérie, Baatallah, Nesrine, Hinzpeter, Alexandre, Golec, Anita, Touqui, Lhousseine, Nassif, Xavier, Galietta, Luis J. V, Planelles, Gabrielle, Sallenave, Jean-Michel, Edelman, Aleksander, Sermet-Gaudelus, Isabelle
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 24.04.2019
Nature Publishing Group
Subjects:
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Acidification
Antimicrobial Cationic Peptides - pharmacology
Antimicrobial peptides
Bicarbonates
Bicarbonates - chemistry
Bicarbonates - metabolism
Bronchi - cytology
Cell Line
Cell lines
Cells, Cultured
Child
Child, Preschool
Cystic fibrosis
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Cystic Fibrosis - microbiology
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Defects
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Epithelial Cells - microbiology
H(+)-K(+)-Exchanging ATPase - metabolism
Human health and pathology
Humanities and Social Sciences
Humans
Hydrogen-Ion Concentration
Immunology
Infant
Infant, Newborn
Infections
Life Sciences
Morbidity
multidisciplinary
Neonates
Ouabain
Peptides
pH effects
Pulmonology and respiratory tract
Respiratory Mucosa - chemistry
Respiratory Mucosa - metabolism
Respiratory Mucosa - microbiology
Respiratory tract
Science
Science (multidisciplinary)
Secretion
Staphylococcal Infections - metabolism
Staphylococcal Infections - microbiology
Staphylococcal Infections - prevention & control
Staphylococcus aureus - drug effects
Staphylococcus aureus - physiology
Sulfate Transporters - metabolism
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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.
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PMCID: PMC6482305
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-42751-4