Abstract
The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ∼100 SNPs/year–∼40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections.
Highlights
The opportunistic pathogen Pseudomonas aeruginosa is found in many environments and can cause acute or chronic infections in a range of hosts from protozoans to plants to humans [1,2]
Genetic adaptation has been shown to play a major role in successful establishment of long-term chronic P. aeruginosa infections of cystic fibrosis (CF) patients, and natural selection acts on these bacteria in CF airways to accommodate the fixation of mutations that cause beneficial phenotypic changes [7,8,9]
We evaluated the genomic changes undergone by mutator populations of P. aeruginosa obtained from single sputum samples from two chronically infected CF patients, and found that mutators completely dominated the infecting population in both patients
Summary
The opportunistic pathogen Pseudomonas aeruginosa is found in many environments and can cause acute or chronic infections in a range of hosts from protozoans to plants to humans [1,2]. Patients with cystic fibrosis (CF) are highly susceptible to chronic colonization by P. aeruginosa, which is frequently fatal because of a persistent inflammatory response leading to gradual decline of lung function [3,4]. Genetic adaptation has been shown to play a major role in successful establishment of long-term chronic P. aeruginosa infections of CF patients, and natural selection acts on these bacteria in CF airways to accommodate the fixation of mutations that cause beneficial phenotypic changes [7,8,9]. A trait frequently observed in chronic infections is an increased mutation rate leading to a mutator phenotype [13,14]. P. aeruginosa from chronically infected CF airways was the first natural model to reveal a high proportion of mutators in contrast
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