LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation
Open Access
- 10 March 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 17 (3), e1009375
- https://doi.org/10.1371/journal.ppat.1009375
Abstract
Pseudomonas aeruginosa causes chronic airway infections, a major determinant of lung inflammation and damage in cystic fibrosis (CF). Loss-of-function lasR mutants 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 how lasR mutants modulate airway epithelial membrane bound ICAM-1 (mICAM-1), a surface adhesion molecule, and determined its impact on neutrophilic inflammation in vitro and in 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 that lasR mutant-infected mice displayed greater airway epithelial ICAM-1 expression and increased neutrophilic pulmonary inflammation. Our findings provide new insights into the intricate interplay between lasR mutants, LasR-regulated proteases and airway epithelial ICAM-1 expression, and reveal a new mechanism involved in the exaggerated inflammatory response induced by lasR mutants.Funding Information
- Deutscher Akademischer Austauschdienst
- Fonds de Recherche du Québec - Santé
- Cystic Fibrosis Canada (2469)
- Canadian Institutes of Health Research (PJT-148827)
- Vertex Pharmaceuticals (Cystic Fibrosis Research Innovation Award)
This publication has 103 references indexed in Scilit:
- Evolutionary remodeling of global regulatory networks during long-term bacterial adaptation to human hostsProceedings of the National Academy of Sciences of the United States of America, 2013
- Strain-dependent diversity in the Pseudomonas aeruginosa quorum-sensing regulonProceedings of the National Academy of Sciences of the United States of America, 2012
- Cooperation and virulence of clinical Pseudomonas aeruginosa populationsProceedings of the National Academy of Sciences of the United States of America, 2009
- Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progressionJournal of Cystic Fibrosis, 2009
- Nutritional Cues ControlPseudomonas aeruginosaMulticellular Behavior in Cystic Fibrosis SputumJournal of Bacteriology, 2007
- Social cheating in Pseudomonas aeruginosa quorum sensingProceedings of the National Academy of Sciences of the United States of America, 2007
- Quorum Sensing Regulates Denitrification in Pseudomonas aeruginosa PAO1Journal of Bacteriology, 2007
- Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patientsMolecular Microbiology, 2007
- Evolving stealth: Genetic adaptation of Pseudomonas aeruginosa during cystic fibrosis infectionsProceedings of the National Academy of Sciences of the United States of America, 2006
- Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patientsProceedings of the National Academy of Sciences of the United States of America, 2006