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

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 () and Gregory P. Priebe ()
Additional contact information
Alexandra J. Poret: Massachusetts Institute of Technology
Matthew Schaefers: Boston Children’s Hospital
Christina Merakou: Boston Children’s Hospital
Kathryn E. Mansour: Boston Children’s Hospital
Connor D. Ahern: Boston Children’s Hospital
Georgia K. Lagoudas: Massachusetts Institute of Technology
Alyssa Haynes: Massachusetts Institute of Technology
Ashley R. Cross: Emory University School of Medicine
Joanna B. Goldberg: Emory University School of Medicine
Roy Kishony: Technion–Israel Institute of Technology
Ahmet Z. Uluer: Boston Children’s Hospital
Alexander J. McAdam: Boston Children’s Hospital
Paul C. Blainey: Massachusetts Institute of Technology
Sara O. Vargas: Harvard Medical School
Tami D. Lieberman: Massachusetts Institute of Technology
Gregory P. Priebe: Boston Children’s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61168-4

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