title: Stage-specific adaptation of hypermutable Pseudomonas aeruginosa isolates during chronic pulmonary infection in patients with cystic fibrosis.
abstract: BACKGROUND
  Pseudomonas aeruginosa (PA) strains with defective DNA mismatch repair genes generate numerous bacterial variants because of high mutation rates. In cystic fibrosis (CF), such mutator strains may lead to the rapid selection of survivors that are specifically adapted to the hostile environment of the inflamed CF lung.
  
  
  METHODS
  Genotypes and phenotypes of 111 PA variants descending from 3 distinct mutator strains obtained from 3 patients with CF were systematically characterized.
  
  
  RESULTS
  We demonstrated that PA mutS isolates accumulated in the CF lung during the observation period of 3-6 years, with dominance during the final stage of the disease. Mutator strains from the final stage of disease were multiresistant and had lost a set of established virulence-associated traits, including cytotoxicity for bronchial epithelial cells (Calu-3) and macrophages (J774). This pathoadaptation was associated with the loss of survival capacity in a typical environmental habitat, such as tap water. Strikingly, nonmutator strains that maintained their virulence potential persisted as a minority, probably with a preference for the lower airways.
  
  
  CONCLUSIONS
  Mutator strains may evolve from the initially infecting PA strain and generate numerous variants with a loss of destructive virulence factors, probably because of selection for improved survival in the deteriorated CF lung but at the expense of the ability to live freely.
authors.affiliation: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, Munich, Germany. hogardt@mvp.uni-muenchen.de
authors.forename: Michael
authors.initials: M
authors.lastname: Hogardt
authors.forename: Christina
authors.initials: C
authors.lastname: Hoboth
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmoldt
authors.forename: Christine
authors.initials: C
authors.lastname: Henke
authors.forename: Lutz
authors.initials: L
authors.lastname: Bader
authors.forename: Jürgen
authors.initials: J
authors.lastname: Heesemann
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000382:microbiology*; D004260:DNA Repair; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents