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Sci Adv. 2015 Jul;1(6). pii: e1500199. Epub 2015 Jul 31.

Cystic fibrosis-adapted Pseudomonas aeruginosa quorum sensing lasR mutants cause hyperinflammatory responses.

Author information

1
Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A, 2B4 Canada.
2
Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
3
Department of Microbiology, University of Washington, Seattle, WA 98195, USA ; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
4
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
5
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
6
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
7
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
8
McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
9
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9, Canada.
10
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.

Abstract

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogen Pseudomonas aeruginosa and severe neutrophilic pulmonary inflammation. P. aeruginosa undergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator gene lasR commonly arise. We sought to define how mutations in lasR alter host-pathogen relationships. We demonstrate that lasR mutants 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, lasR mutant-infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected with lasR mutants 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.

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