title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Stanton
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Bonita
authors.initials: B
authors.lastname: Coutermarsh
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Roxanna
authors.initials: R
authors.lastname: Barnaby
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hogan
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000382:microbiology; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D009154:Mutation / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D002712:Chlorides; D004268:DNA-Binding Proteins; C474280:FEV protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor