LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation

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Abstract
Pseudomonas aeruginosacauses chronic airway infections, a major determinant of lung inflammation and damage in cystic fibrosis (CF). Loss-of-functionlasRmutants commonly arise during chronic CF infections, are associated with accelerated lung function decline in CF patients and induce exaggerated neutrophilic inflammation in model systems. In this study, we investigated howlasRmutants modulate airway epithelial membrane bound ICAM-1 (mICAM-1), a surface adhesion molecule, and determined its impact on neutrophilic inflammationin vitroandin vivo. We demonstrated that LasR-deficient strains induce increased mICAM-1 levels in airway epithelial cells compared to wild-type strains, an effect attributable to the loss of mICAM-1 degradation by LasR-regulated proteases and associated with enhanced neutrophil adhesion. In a subacute airway infection model, we also observed thatlasRmutant-infected mice displayed greater airway epithelial ICAM-1 expression and increased neutrophilic pulmonary inflammation. Our findings provide new insights into the intricate interplay betweenlasRmutants, LasR-regulated proteases and airway epithelial ICAM-1 expression, and reveal a new mechanism involved in the exaggerated inflammatory response induced bylasRmutants.
Funding Information
  • Deutscher Akademischer Austauschdienst
  • Santé
  • Cystic Fibrosis Canada (2469)
  • Canadian Institutes of Health Research (PJT-148827)
  • Vertex Pharmaceuticals (Cystic Fibrosis Research Innovation Award)

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