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<p>Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen <i>Burkholderia dolosa</i> overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected cystic fibrosis patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, convergent mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their <i>B. dolosa</i> communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization reveals that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven phenotypic alternation may be underestimated without dense temporal sampling, particularly for microbes with prolonged infection or colonization.</p>

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De novo mutations mediate phenotypic switching in an opportunistic human lung pathogen

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月23日

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  • Alexandra J. Poret,
  • Matthew Schaefers,
  • Christina Merakou,
  • Kathryn E. Mansour,
  • Connor D. Ahern,
  • Georgia K. Lagoudas,
  • Alyssa Haynes,
  • Ashley R. Cross,
  • Joanna B. Goldberg,
  • Roy Kishony,
  • Ahmet Z. Uluer,
  • Alexander J. McAdam,
  • Paul C. Blainey,
  • Sara O. Vargas,
  • Tami D. Lieberman,
  • Gregory P. Priebe

摘要

Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen Burkholderia dolosa overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected cystic fibrosis patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, convergent mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their B. dolosa communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization reveals that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven phenotypic alternation may be underestimated without dense temporal sampling, particularly for microbes with prolonged infection or colonization.