Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells.

Abstract

BACKGROUND:

P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770.

METHODS AND RESULTS:

F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR.

CONCLUSION:

The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials.

• Authors: Bruce A Stanton, Bonita Coutermarsh, Roxanna Barnaby, Deborah Hogan
• Journal: PloS one (PLoS One) Vol. 10 Issue 5 Pg. e0127742 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26018799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Benzodioxoles
• CFTR protein, human
• Chlorides
• DNA-Binding Proteins
• FEV protein, human
• Nuclear Proteins
• Transcription Factors
• Cystic Fibrosis Transmembrane Conductance Regulator
• lumacaftor

Topics

• Aminopyridines (pharmacology)
• Benzodioxoles (pharmacology)
• Bronchi (drug effects, metabolism, microbiology)
• Cell Line
• Cell Membrane (drug effects, microbiology)
• Chlorides (metabolism)
• Cystic Fibrosis (metabolism, microbiology)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• DNA-Binding Proteins (metabolism)
• Epithelial Cells (drug effects, metabolism, microbiology)
• Humans
• Mutation (drug effects)
• Nuclear Proteins (metabolism)
• Pseudomonas Infections (metabolism, microbiology)
• Pseudomonas aeruginosa (physiology)
• Transcription Factors