Cystic fibrosis-adapted quorum sensing mutants cause hyperinflammatory responses.

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