LaFayette et al. Sci. Adv. 2015;1:e1500199 31 July 2015
Shantelle L. LaFayette1, Daniel Houle2, Trevor Beaudoin2, Gabriella Wojewodka2, Danuta Radzioch2, Lucas R. Hoffman3,4, Jane L. Burns4, Ajai A. Dandekar3, Nicole E. Smalley3, Josephine R. Chandler5, James E. Zlosnik6, David P. Speert6, Joanie Bernier7, Elias Matouk7, Emmanuelle Brochiero8, Simon Rousseau2, Dao Nguyen1,2,7
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.
