Quorum Sensing Down-Regulation Counteracts the Negative Impact of Pseudomonas aeruginosa on CFTR Channel Expression, Function and Rescue in Human Airway Epithelial Cells
Authors
Émilie Maillé, Manon Ruffin, Damien Adam, Hatem Messaoud, Shantelle L. Lafayette, Geoffrey McKay, Dao Nguyen and Emmanuelle Brochiero
Institution
Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
Country
Canada
Year
2017
Journal
Frontiers in Cellular and Infection Microbiology
Abstract
The function of cystic fibrosis transmembrane conductance regulator (CFTR) channels
is crucial in human airways. However unfortunately, chronic Pseudomonas aeruginosa
infection has been shown to impair CFTR proteins in non-CF airway epithelial cells
(AEC) and to alter the efficiency of new treatments with CFTR modulators designed
to correct the basic CFTR default in AEC from cystic fibrosis (CF) patients carrying the
F508del mutation. Our aim was first to compare the effect of laboratory strains, clinical
isolates, engineered and natural mutants to determine the role of the LasR quorum
sensing system in CFTR impairment, and second, to test the efficiency of a quorum
sensing inhibitor to counteract the deleterious impact of P. aeruginosa both on wt-CFTR
and on the rescue of F508del-CFTR by correctors. We first report that exoproducts
from either the laboratory PAO1 strain or a clinical ≪Early≫ isolate (from an early
stage of infection) altered CFTR expression, localization and function in AEC expressing
wt-CFTR. Genetic inactivation of the quorum-sensing LasR in PAO1 (PAO11lasR) or
in a natural clinical mutant (≪Late≫ CF-adapted clinical isolate) abolished wt-CFTR
impairment. PAO1 exoproducts also dampened F508del-CFTR rescue by VRT-325
or Vx-809 correctors in CF cells, whereas PAO11lasR had no impact. Importantly,
treatment of P. aeruginosa cultures with a quorumsensing inhibitor (HDMF) prevented the
negative effect of P. aeruginosa exoproducts on wt-CFTR and preserved CFTR rescue
by correctors in CF AEC. These findings indicate that LasR-interfering strategies could
be of benefits to counteract the deleterious effect of P. aeruginosa in infected patients.