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Journal of Bacteriology, December 2008, p. 7910-7917, Vol. 190, No. 24
0021-9193/08/$08.00+0     doi:10.1128/JB.01147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genetic Adaptation of Pseudomonas aeruginosa to the Airways of Cystic Fibrosis Patients Is Catalyzed by Hypermutation {triangledown} ,{dagger}

A. Mena,1 E. E. Smith,2 J. L. Burns,3 D. P. Speert,4 S. M. Moskowitz,3 J. L. Perez,1 and A. Oliver1*

Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain,1 Fred Hutchinson Cancer Research Center, Seattle, Wasnington,2 Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington,3 Division of Infectious and Immunological Diseases, University of British Columbia and Child and Family Research Institute, BC Children's Hospital, Vancouver, British Columbia, Canada4

Received 14 August 2008/ Accepted 1 October 2008

In previous work (E. E. Smith, D. G. Buckley, Z. Wu, C. Saenphimmachack, L. R. Hoffman, D. A. D'Argenio, S. I. Miller, B. W. Ramsey, D. P. Speert, S. M. Moskowitz, J. L. Burns, R. Kaul, and M. V. Olson, Proc. Natl. Acad. Sci. USA 103:8487-8492, 2006) it was shown that Pseudomonas aeruginosa undergoes intense genetic adaptation during chronic respiratory infection (CRI) in cystic fibrosis (CF) patients. We used the same collection of isolates to explore the role of hypermutation in this process, since one of the hallmarks of CRI is the high prevalence of DNA mismatch repair (MMR) system-deficient mutator strains. The presence of mutations in 34 genes (many of them positively linked to adaptation in CF patients) in the study collection of 90 P. aeruginosa isolates obtained longitudinally from 29 CF patients was not homogeneous; on the contrary, mutations were significantly concentrated in the mutator lineages, which represented 17% of the isolates (87% MMR deficient). While sequential nonmutator lineages acquired a median of only 0.25 mutation per year of infection, mutator lineages accumulated more than 3 mutations per year. On the whole-genome scale, data for the first fully sequenced late CF isolate, which was also shown to be an MMR-deficient mutator, also support these findings. Moreover, for the first time the predicted amplification of mutator populations due to hitchhiking with adaptive mutations in the course of natural human infections is clearly documented. Interestingly, increased accumulation of mutations in mutator lineages was not a consequence of overrepresentation of mutations in genes involved in antimicrobial resistance, the only adaptive trait linked so far to hypermutation in CF patients, demonstrating that hypermutation also plays a major role in P. aeruginosa genome evolution and adaptation during CRI.

* Corresponding author. Mailing address: Servicio de Microbiología, Hospital Son Dureta, C. Andrea Doria no. 55, 07014 Palma de Mallorca, Spain. Phone and fax: 34 971 175 185. E-mail: aoliver{at}hsd.es

{triangledown} Published ahead of print on 10 October 2008.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

Journal of Bacteriology, December 2008, p. 7910-7917, Vol. 190, No. 24
0021-9193/08/$08.00+0     doi:10.1128/JB.01147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Foweraker, J. (2009). Recent advances in the microbiology of respiratory tract infection in cystic fibrosis. Br Med Bull 89: 93-110 [Abstract] [Full Text]  


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