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P. aeruginosa Infected 3D Co-Culture of Bronchial Epithelial Cells and Macrophages at Air-Liquid Interface for Preclinical Evaluation of Anti-Infectives
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Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells

Bruce A Stanton1, Bonita Coutermarsh1, Roxanna Barnaby1

  • 1Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Plos One
|May 29, 2015
PubMed
Abstract

Insights

Pseudomonas aeruginosa infection reduces the effectiveness of CFTR modulator drugs like VX-809 and VX-770 in cystic fibrosis (CF) patients. This bacterial lung infection impairs drug-stimulated chloride secretion, potentially explaining modest clinical trial results.

Area of Science:

  • Pulmonary Medicine
  • Microbiology
  • Genetics

Background:

  • Cystic Fibrosis (CF) affects 85% of adult patients with chronic lung infections by *Pseudomonas aeruginosa*.
  • P. aeruginosa infection reduces wild-type CFTR chloride secretion in airway epithelial cells.
  • Investigational drugs VX-809 and VX-770 improve F508del-CFTR chloride secretion and FEV1 in CF patients.

Purpose of the Study:

  • To investigate the impact of *P. aeruginosa* infection on VX-809 and VX-770 stimulated F508del-CFTR chloride secretion.
  • To determine if *P. aeruginosa* reduces the clinical efficacy of these CFTR modulator drugs.

Main Methods:

  • Exposure of F508del-CFBE and primary CF-HBE cells to VX-809 alone or in combination with VX-770.
  • Measurement of F508del-CFTR chloride secretion using Ussing chambers.
  • Assessment of F508del-CFTR abundance via cell surface biotinylation and western blot analysis.

Main Results:

  • *P. aeruginosa* (including clinical isolates) significantly reduced VX-809 and VX-809 + VX-770 stimulated F508del-CFTR chloride secretion.
  • Bacterial infection also decreased plasma membrane F508del-CFTR levels.
  • Multiple strains of *P. aeruginosa* demonstrated this inhibitory effect.

Conclusions:

  • *P. aeruginosa* infection diminishes the chloride secretion stimulated by VX-809 and VX-809 + VX-770 in F508del-CFTR cells.
  • This interaction may partially explain the modest clinical efficacy observed with VX-809 + VX-770 in CF patients.
  • Targeting *P. aeruginosa* infection could enhance the effectiveness of CFTR modulator therapies.

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