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Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae MRR1
The evolution of pathogens in response to selective pressures present during chronic infections can influence their persistence and virulence and the outcomes of antimicrobial therapy. Because subpopulations within an infection can be spatially separated and the host environment can fluctuate, an ap...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092287/ https://www.ncbi.nlm.nih.gov/pubmed/33785623 http://dx.doi.org/10.1128/mBio.03328-20 |
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author | Demers, Elora G. Stajich, Jason E. Ashare, Alix Occhipinti, Patricia Hogan, Deborah A. |
author_facet | Demers, Elora G. Stajich, Jason E. Ashare, Alix Occhipinti, Patricia Hogan, Deborah A. |
author_sort | Demers, Elora G. |
collection | PubMed |
description | The evolution of pathogens in response to selective pressures present during chronic infections can influence their persistence and virulence and the outcomes of antimicrobial therapy. Because subpopulations within an infection can be spatially separated and the host environment can fluctuate, an appreciation of the pathways under selection may be most easily revealed through the analysis of numerous isolates from single infections. Here, we continued our analysis of a set of clonally derived Clavispora (Candida) lusitaniae isolates from a single chronic lung infection with a striking enrichment in the number of alleles of MRR1. Genetic and genomic analyses found evidence for repeated acquisition of gain-of-function mutations that conferred constitutive Mrr1 activity. In the same population, there were multiple alleles with both gain-of-function mutations and secondary suppressor mutations that either attenuated or abolished the constitutive activity, suggesting the presence of counteracting selective pressures. Our studies demonstrated trade-offs between high Mrr1 activity, which confers resistance to the antifungal fluconazole, host factors, and bacterial products through its regulation of MDR1, and resistance to hydrogen peroxide, a reactive oxygen species produced in the neutrophilic environment associated with this infection. This inverse correlation between high Mrr1 activity and hydrogen peroxide resistance was observed in multiple Candida species and in serially collected populations from this individual over 3 years. These data lead us to propose that dynamic or variable selective pressures can be reflected in population genomics and that these dynamics can complicate the drug resistance profile of the population. |
format | Online Article Text |
id | pubmed-8092287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-80922872021-05-04 Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae MRR1 Demers, Elora G. Stajich, Jason E. Ashare, Alix Occhipinti, Patricia Hogan, Deborah A. mBio Research Article The evolution of pathogens in response to selective pressures present during chronic infections can influence their persistence and virulence and the outcomes of antimicrobial therapy. Because subpopulations within an infection can be spatially separated and the host environment can fluctuate, an appreciation of the pathways under selection may be most easily revealed through the analysis of numerous isolates from single infections. Here, we continued our analysis of a set of clonally derived Clavispora (Candida) lusitaniae isolates from a single chronic lung infection with a striking enrichment in the number of alleles of MRR1. Genetic and genomic analyses found evidence for repeated acquisition of gain-of-function mutations that conferred constitutive Mrr1 activity. In the same population, there were multiple alleles with both gain-of-function mutations and secondary suppressor mutations that either attenuated or abolished the constitutive activity, suggesting the presence of counteracting selective pressures. Our studies demonstrated trade-offs between high Mrr1 activity, which confers resistance to the antifungal fluconazole, host factors, and bacterial products through its regulation of MDR1, and resistance to hydrogen peroxide, a reactive oxygen species produced in the neutrophilic environment associated with this infection. This inverse correlation between high Mrr1 activity and hydrogen peroxide resistance was observed in multiple Candida species and in serially collected populations from this individual over 3 years. These data lead us to propose that dynamic or variable selective pressures can be reflected in population genomics and that these dynamics can complicate the drug resistance profile of the population. American Society for Microbiology 2021-03-30 /pmc/articles/PMC8092287/ /pubmed/33785623 http://dx.doi.org/10.1128/mBio.03328-20 Text en Copyright © 2021 Demers et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Demers, Elora G. Stajich, Jason E. Ashare, Alix Occhipinti, Patricia Hogan, Deborah A. Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae MRR1 |
title | Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae
MRR1 |
title_full | Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae
MRR1 |
title_fullStr | Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae
MRR1 |
title_full_unstemmed | Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae
MRR1 |
title_short | Balancing Positive and Negative Selection: In Vivo Evolution of Candida lusitaniae
MRR1 |
title_sort | balancing positive and negative selection: in vivo evolution of candida lusitaniae
mrr1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092287/ https://www.ncbi.nlm.nih.gov/pubmed/33785623 http://dx.doi.org/10.1128/mBio.03328-20 |
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