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Evolution of Burkholderia pseudomallei in recurrent melioidosis
Hillary S Hayden1, Regina Lim, Mitchell J Brittnacher
1Department of Microbiology, University of Washington, Seattle, Washington, United States of America. hhayden@u.washington.edu
Abstract:
Burkholderia pseudomallei, the etiologic agent of human melioidosis, is capable of causing severe acute infection with overwhelming septicemia leading to death. A high rate of recurrent disease occurs in adult patients, most often due to recrudescence of the initial infecting strain. Pathogen persistence and evolution during such relapsing infections are not well understood. Bacterial cells present in the primary inoculum and in late infections may differ greatly, as has been observed in chronic disease, or they may be genetically similar. To test these alternative models, we conducted whole-genome comparisons of clonal primary and relapse B. pseudomallei isolates recovered six months to six years apart from four adult Thai patients. We found differences within each of the four pairs, and some, including a 330 Kb deletion, affected substantial portions of the genome. Many of the changes were associated with increased antibiotic resistance. We also found evidence of positive selection for deleterious mutations in a TetR family transcriptional regulator from a set of 107 additional B. pseudomallei strains. As part of the study, we sequenced to base-pair accuracy the genome of B. pseudomallei strain 1026b, the model used for genetic studies of B. pseudomallei pathogenesis and antibiotic resistance. Our findings provide new insights into pathogen evolution during long-term infections and have important implications for the development of intervention strategies to combat recurrent melioidosis.
Insights
Recurrent melioidosis involves significant genetic changes in Burkholderia pseudomallei, including large deletions and mutations conferring antibiotic resistance. Understanding this pathogen evolution is key to preventing relapsing infections.
Area of Science:
- Microbiology and Infectious Diseases
- Genomics and Pathogen Evolution
Background:
- Melioidosis, caused by Burkholderia pseudomallei, can lead to severe septicemia and death.
- Recurrent melioidosis in adults often results from the initial infecting strain, but pathogen evolution during these relapses is poorly understood.
- Bacterial populations may diverge significantly or remain genetically similar between primary and relapse infections.
Purpose of the Study:
- To investigate the genetic divergence and evolution of Burkholderia pseudomallei during recurrent melioidosis.
- To compare whole-genome sequences of primary and relapse isolates to understand pathogen persistence and adaptation.
- To identify genetic changes associated with increased antibiotic resistance and potential therapeutic targets.
Main Methods:
- Whole-genome comparisons of clonal primary and relapse Burkholderia pseudomallei isolates from four Thai patients, separated by 6 months to 6 years.
- Sequencing of the Burkholderia pseudomallei strain 1026b genome to base-pair accuracy.
- Analysis of genetic changes, including deletions and mutations, and assessment for positive selection in additional strains.
Main Results:
- Significant genetic differences were observed between primary and relapse isolates within each of the four patient pairs.
- A substantial 330 Kb deletion was identified in one isolate pair, affecting large genomic regions.
- Many genetic alterations were linked to increased antibiotic resistance; evidence of positive selection for deleterious mutations was also found.
Conclusions:
- Pathogen evolution, including substantial genomic alterations and acquisition of antibiotic resistance, occurs during long-term, relapsing melioidosis.
- These findings provide critical insights into the mechanisms of Burkholderia pseudomallei persistence and adaptation.
- Understanding pathogen evolution is essential for developing effective intervention strategies against recurrent melioidosis.
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