Metabolic basis for the evolution of a common pathogenic Pseudomonas aeruginosa variant
- Geisel School of Medicine at Dartmouth, United States
- Dartmouth-Hitchock Medical Center, United States
Abstract
Microbes frequently evolve in reproducible ways. Here, we show that differences in specific metabolic regulation rather than inter-strain interactions explain the frequent presence of lasR loss-of-function mutations in the bacterial pathogen Pseudomonas aeruginosa. While LasR contributes to virulence through its role in quorum sensing, lasR mutants have been associated with more severe disease. A model based on the intrinsic growth kinetics for a wild type strain and its LasR- derivative, in combination with an experimental evolution based genetic screen and further genetics analyses, indicated that differences in metabolism were sufficient to explain the rise of these common mutant types. The evolution of LasR- lineages in laboratory and clinical isolates depended on activity of the two-component system CbrAB, which modulates substrate prioritization through the catabolite repression control pathway. LasR- lineages frequently arise in cystic fibrosis lung infections and their detection correlates with disease severity. Our analysis of bronchoalveolar lavage fluid metabolomes identified compounds that negatively correlate with lung function, and we show that these compounds support enhanced growth of LasR- cells in a CbrB-controlled manner. We propose that in vivo metabolomes contribute to pathogen evolution, which may influence the progression of disease and its treatment.
Data availability
All sequencing data is available on the Sequence Read Archive with accession number PRJNA786588 upon publication. All data generated or analyzed and all code used during this study are included in the manuscript or associated files.
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Pool Seq of Experimentally Evolved P. aeruginosa PA14 populations in LBNCBI Sequence Read Archive, PRJNA786588.
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Author details
Funding
Cystic Fibrosis Foundation (HOGAN19G0)
- Dallas L Mould
- Deborah A Hogan
Cystic Fibrosis Foundation (ASHARE20P0)
- Alix Ashare
Cystic Fibrosis Foundation (STANTO19R0)
- Daniel Schultz
Cystic Fibrosis Foundation (T32AI007519)
- Dallas L Mould
National Institutes of Health (R01HL122372)
- Alix Ashare
National Institutes of Health (GM130454)
- Mirjana Stevanovic
- Daniel Schultz
National Institutes of Health (P20GM113132)
- Dallas L Mould
- Deborah A Hogan
National Institutes of Health (DK117469)
- Dallas L Mould
- Alix Ashare
- Daniel Schultz
- Deborah A Hogan
National Institutes of Health (P30CA023108)
- Dallas L Mould
- Alix Ashare
- Daniel Schultz
- Deborah A Hogan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Mould et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Metabolic basis for the evolution of a common pathogenic Pseudomonas aeruginosa variant
eLife 11:e76555.
https://doi.org/10.7554/eLife.76555
