Genetic Adaptation of Pseudomonas aeruginosa to the Airways of Cystic Fibrosis Patients Is Catalyzed by Hypermutation

被引:187
作者
Mena, A. [1 ,2 ]
Smith, E. E. [3 ]
Burns, J. L. [4 ]
Speert, D. P. [5 ,6 ]
Moskowitz, S. M. [4 ]
Perez, J. L. [1 ,2 ]
Oliver, A. [1 ,2 ]
机构
[1] Hosp Son Dureta, Microbiol Serv, Palma de Mallorca 07014, Spain
[2] Hosp Son Dureta, Unidad Invest, IUNICS, Palma de Mallorca 07014, Spain
[3] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA
[4] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA
[5] Univ British Columbia, Div Infect & Immunol Dis, Vancouver, BC V5Z 1M9, Canada
[6] BC Childrens Hosp, Child & Family Res Inst, Vancouver, BC, Canada
关键词
D O I
10.1128/JB.01147-08
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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收藏
页码:7910 / 7917
页数:8
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