title: Quorum-sensing inhibition abrogates the deleterious impact of Pseudomonas aeruginosa on airway epithelial repair.
abstract: Chronic Pseudomonas aeruginosa lung infections are associated with progressive epithelial damage and lung function decline. In addition to its role in tissue injury, the persistent presence of P. aeruginosa-secreted products may also affect epithelial repair ability, raising the need for new antivirulence therapies. The purpose of our study was to better understand the outcomes of P. aeruginosa exoproducts exposure on airway epithelial repair processes to identify a strategy to counteract their deleterious effect. We found that P. aeruginosa exoproducts significantly decreased wound healing, migration, and proliferation rates, and impaired the ability of directional migration of primary non-cystic fibrosis (CF) human airway epithelial cells. Impact of exoproducts was inhibited after mutations in P. aeruginosa genes that encoded for the quorum-sensing (QS) transcriptional regulator, LasR, and the elastase, LasB, whereas impact was restored by LasB induction in ΔlasR mutants. P. aeruginosa purified elastase also induced a significant decrease in non-CF epithelial repair, whereas protease inhibition with phosphoramidon prevented the effect of P. aeruginosa exoproducts. Furthermore, treatment of P. aeruginosa cultures with 4-hydroxy-2,5-dimethyl-3(2H)-furanone, a QS inhibitor, abrogated the negative impact of P. aeruginosa exoproducts on airway epithelial repair. Finally, we confirmed our findings in human airway epithelial cells from patients with CF, a disease featuring P. aeruginosa chronic respiratory infection. These data demonstrate that secreted proteases under the control of the LasR QS system impair airway epithelial repair and that QS inhibitors could be of benefit to counteract the deleterious effect of P. aeruginosa in infected patients.-Ruffin, M., Bilodeau, C., Maillé, É., LaFayette, S. L., McKay, G. A., Trinh, N. T. N., Beaudoin, T., Desrosiers, M.-Y., Rousseau, S., Nguyen, D., Brochiero, E. Quorum-sensing inhibition abrogates the deleterious impact of Pseudomonas aeruginosa on airway epithelial repair.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada;
authors.forename: Manon
authors.initials: M
authors.lastname: Ruffin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada;
authors.forename: Claudia
authors.initials: C
authors.lastname: Bilodeau
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada;
authors.forename: Émilie
authors.initials: É
authors.lastname: Maillé
authors.affiliation: The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Shantelle L
authors.initials: SL
authors.lastname: LaFayette
authors.affiliation: The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: McKay
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada;
authors.forename: Nguyen Thu Ngan
authors.initials: NT
authors.lastname: Trinh
authors.affiliation: The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Beaudoin
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada;
authors.forename: Martin-Yvon
authors.initials: MY
authors.lastname: Desrosiers
authors.affiliation: The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: The Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Dao
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada; emmanuelle.brochiero@umontreal.ca.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Brochiero
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000382:microbiology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006801:Humans; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology; D012137:Respiratory System
chemical_list: D001426:Bacterial Proteins
keywords: LasB elastase; LasR; cystic fibrosis; furanone QSI; infection