Cystic fibrosis–adapted <i>Pseudomonas aeruginosa</i> quorum sensing <i>lasR</i> mutants cause hyperinflammatory responses

Abstract

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