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Evolutionary trade-offs associated with loss of PmrB function in host-adapted Pseudomonas aeruginosa
Laura Bricio-Moreno1, Victoria H Sheridan1, Ian Goodhead2
1Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.
Abstract:
Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed early-acquired mutations in pmrB, encoding the sensor kinase of a two-component system that promoted establishment and persistence of infection. Here, using proteomics, we show downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production in pmrB mutants, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants are susceptible to antibiotic treatment but show enhanced adherence to airway epithelial cells, resistance to lysozyme treatment, and downregulate host CFTR expression. We propose that P. aeruginosa pmrB mutations in CF patients are subject to an evolutionary trade-off, leading to enhanced colonisation potential, CFTR inhibition, and resistance to host defences, but also to increased susceptibility to antibiotics.
Insights
Mutations in the Pseudomonas aeruginosa pmrB gene enhance airway colonization and host defense resistance in cystic fibrosis patients. However, these pmrB mutations also increase susceptibility to antibiotic treatments.
Area of Science:
- Microbiology
- Genetics
- Infectious Diseases
Background:
- Pseudomonas aeruginosa is a key pathogen in cystic fibrosis (CF) lung infections.
- Host-adapted P. aeruginosa strains colonize the upper airway, establishing chronic infections.
- Early mutations in pmrB promote infection establishment and persistence.
Purpose of the Study:
- To investigate the functional consequences of pmrB mutations in P. aeruginosa.
- To understand the evolutionary trade-offs associated with pmrB mutations in CF lung infections.
Main Methods:
- Proteomic analysis of pmrB mutants compared to wild-type P. aeruginosa LESB65.
- Assessment of adherence to airway epithelial cells.
- Evaluation of resistance to lysozyme treatment.
- Measurement of CFTR expression inhibition.
Main Results:
- pmrB mutants showed downregulated proteins in LPS biosynthesis, antimicrobial resistance, and phenazine production.
- Upregulated proteins in pmrB mutants were involved in adherence, lysozyme resistance, and CFTR inhibition.
- Mutants exhibited enhanced adherence, lysozyme resistance, and CFTR downregulation.
- pmrB mutants were susceptible to antibiotic treatment.
Conclusions:
- P. aeruginosa pmrB mutations in CF patients lead to an evolutionary trade-off.
- Mutations enhance colonization, CFTR inhibition, and host defense resistance.
- These adaptations come at the cost of increased antibiotic susceptibility.
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