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Metabolic basis for the evolution of a common pathogenic Pseudomonas aeruginosa variant

Dallas L. Mould, Mirjana Stevanovic, Alix Ashare, Daniel Schultz, View ORCID ProfileDeborah A Hogan
doi: https://doi.org/10.1101/2022.01.14.476307
Dallas L. Mould
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH USA
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Mirjana Stevanovic
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH USA
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Alix Ashare
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH USA
2Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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Daniel Schultz
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH USA
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Deborah A Hogan
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH USA
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  • ORCID record for Deborah A Hogan
  • For correspondence: dhogan@dartmouth.edu
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Abstract

Microbes frequently evolve in reproducible ways. Here, we show that differences in specific metabolic regulation explain the frequent presence of lasR loss-of-function mutations in the bacterial pathogen Pseudomonas aeruginosa. While LasR contributes to virulence, 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 are a major driver of pathogen evolution, which may influence the progression of disease and its treatment.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 14, 2022.
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Metabolic basis for the evolution of a common pathogenic Pseudomonas aeruginosa variant
Dallas L. Mould, Mirjana Stevanovic, Alix Ashare, Daniel Schultz, Deborah A Hogan
bioRxiv 2022.01.14.476307; doi: https://doi.org/10.1101/2022.01.14.476307
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Metabolic basis for the evolution of a common pathogenic Pseudomonas aeruginosa variant
Dallas L. Mould, Mirjana Stevanovic, Alix Ashare, Daniel Schultz, Deborah A Hogan
bioRxiv 2022.01.14.476307; doi: https://doi.org/10.1101/2022.01.14.476307

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