title: Airway Epithelial Cell Integrity Protects from Cytotoxicity of Pseudomonas aeruginosa Quorum-Sensing Signals.
abstract: Cell-to-cell communication via gap junctions regulates airway epithelial cell homeostasis and maintains the epithelium host defense. Quorum-sensing molecules produced by Pseudomonas aeruginosa coordinate the expression of virulence factors by this respiratory pathogen. These bacterial signals may also incidentally modulate mammalian airway epithelial cell responses to the pathogen, a process called interkingdom signaling. We investigated the interactions between the P. aeruginosa N-3-oxo-dodecanoyl-L-homoserine lactone (C12) quorum-sensing molecule and human airway epithelial cell gap junctional intercellular communication (GJIC). C12 degradation and its effects on cells were monitored in various airway epithelial cell models grown under nonpolarized and polarized conditions. Its concentration was further monitored in daily tracheal aspirates of colonized intubated patients. C12 rapidly altered epithelial integrity and decreased GJIC in nonpolarized airway epithelial cells, whereas other quorum-sensing molecules had no effect. The effects of C12 were dependent on [Ca(2+)]i and could be prevented by inhibitors of Src tyrosine family and Rho-associated protein kinases. In contrast, polarized airway cells grown on Transwell filters were protected from C12 except when undergoing repair after wounding. In vivo during colonization of intubated patients, C12 did not accumulate, but it paralleled bacterial densities. In vitro C12 degradation, a reaction catalyzed by intracellular paraoxonase 2 (PON2), was impaired in nonpolarized cells, whereas PON2 expression was increased during epithelial polarization. The cytotoxicity of C12 on nonpolarized epithelial cells, combined with its impaired degradation allowing its accumulation, provides an additional pathogenic mechanism for P. aeruginosa infections.
authors.affiliation: 1 Laboratory of Clinical Investigation III.
authors.forename: Davide
authors.initials: D
authors.lastname: Losa
authors.affiliation: 2 Service of Infectious Diseases and Department of Microbiology and Molecular Genetics, and.
authors.forename: Thilo
authors.initials: T
authors.lastname: Köhler
authors.affiliation: 1 Laboratory of Clinical Investigation III.|3 Department of Cell Physiology and Metabolism, Geneva University Hospitals and Medical School of the University of Geneva, Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Bacchetta
authors.affiliation: 1 Laboratory of Clinical Investigation III.|3 Department of Cell Physiology and Metabolism, Geneva University Hospitals and Medical School of the University of Geneva, Geneva, Switzerland.
authors.forename: Joanna Bou
authors.initials: JB
authors.lastname: Saab
authors.affiliation: 3 Department of Cell Physiology and Metabolism, Geneva University Hospitals and Medical School of the University of Geneva, Geneva, Switzerland.
authors.forename: Maud
authors.initials: M
authors.lastname: Frieden
authors.affiliation: 2 Service of Infectious Diseases and Department of Microbiology and Molecular Genetics, and.
authors.forename: Christian
authors.initials: C
authors.lastname: van Delden
authors.affiliation: 1 Laboratory of Clinical Investigation III.|3 Department of Cell Physiology and Metabolism, Geneva University Hospitals and Medical School of the University of Geneva, Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
mesh_terms: D043303:Aryldialkylphosphatase / Q000378:metabolism; D020013:Calcium Signaling; D002450:Cell Communication; D002460:Cell Line; D004847:Epithelial Cells / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology; D006714:Homoserine / Q000031:analogs & derivatives* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007783:Lactones; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D053038:Quorum Sensing; D020545:Respiratory Mucosa / Q000382:microbiology / Q000473:pathology
chemical_list: D007783:Lactones; C085113:Pseudomonas aeruginosa autoinducer; D006714:Homoserine; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human
keywords: Pseudomonas aeruginosa; calcium; cystic fibrosis; gap junctions; quorum sensing