title: Cystic fibrosis-adaptedPseudomonas aeruginosaquorum sensinglasRmutants cause hyperinflammatory responses.
abstract: Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogenPseudomonas aeruginosaand severe neutrophilic pulmonary inflammation.P. aeruginosaundergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator genelasRcommonly arise. We sought to define how mutations inlasRalter host-pathogen relationships. We demonstrate thatlasRmutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease- dependent cytokine degradation. In subacute pulmonary infections,lasRmutant-infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected withlasRmutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A, 2B4 Canada.
authors.forename: Shantelle L
authors.initials: SL
authors.lastname: LaFayette
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Houle
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Beaudoin
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Wojewodka
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Danuta
authors.initials: D
authors.lastname: Radzioch
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA ; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Hoffman
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Burns
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ajai A
authors.initials: AA
authors.lastname: Dandekar
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Smalley
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Josephine R
authors.initials: JR
authors.lastname: Chandler
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: James E
authors.initials: JE
authors.lastname: Zlosnik
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Speert
authors.affiliation: McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Joanie
authors.initials: J
authors.lastname: Bernier
authors.affiliation: McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Elias
authors.initials: E
authors.lastname: Matouk
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Brochiero
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A, 2B4 Canada ; Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada ; McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Dao
authors.initials: D
authors.lastname: Nguyen