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Cystic fibrosis-adapted Pseudomonas aeruginosa quorum sensing lasR mutants cause hyperinflammatory responses

Shantelle L LaFayette1, Daniel Houle2, Trevor Beaudoin2

  • 1Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A, 2B4 Canada.

Science Advances
|October 13, 2015
PubMed

Insights

Mutations in Pseudomonas aeruginosa lasR worsen cystic fibrosis lung disease by increasing inflammation. These bacterial adaptations enhance host inflammatory responses, leading to greater lung damage and disease progression in patients.

Area of Science:

  • Microbiology
  • Immunology
  • Pulmonary Medicine

Background:

  • Cystic fibrosis (CF) lung disease involves chronic Pseudomonas aeruginosa infections and neutrophilic inflammation.
  • P. aeruginosa adapts genetically in the CF lung, frequently acquiring mutations in the lasR quorum sensing regulator gene.

Purpose of the Study:

  • To investigate how lasR mutations in P. aeruginosa affect host-pathogen interactions in CF lung disease.
  • To determine the impact of lasR mutants on host inflammatory responses and disease pathogenesis.

Main Methods:

  • Assessing inflammatory responses in respiratory epithelial cells exposed to lasR mutants.
  • Evaluating pulmonary inflammation and immunopathology in a mouse model of P. aeruginosa infection.
  • Measuring plasma interleukin-8 (IL-8) levels in CF patients infected with lasR mutants.

Main Results:

  • lasR mutants induced exaggerated inflammatory responses in epithelial cells, with increased proinflammatory cytokines.
  • Bacterial protease activity, reduced in lasR mutants, normally degrades cytokines.
  • Infection with lasR mutants led to greater neutrophilic inflammation and immunopathology in mice.
  • CF patients infected with lasR mutants exhibited elevated plasma IL-8 levels.

Conclusions:

  • lasR mutations in P. aeruginosa enhance host inflammatory responses by impairing bacterial protease-dependent cytokine degradation.
  • These bacterial adaptive changes contribute to increased pulmonary inflammation and immunopathology in cystic fibrosis.
  • Bacterial genetic adaptations, such as lasR mutations, may directly worsen lung disease progression in CF patients.

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