title: Antibiotic pressure compensates the biological cost associated with Pseudomonas aeruginosa hypermutable phenotypes in vitro and in a murine model of chronic airways infection.
abstract: OBJECTIVE
  Hypermutable strains of Pseudomonas aeruginosa frequently emerge during chronic airways infection in cystic fibrosis (CF) patients. While the increased accumulation of mutations by hypermutable strains determines a biological cost for the colonization of secondary environments, the mutator phenotypes might confer a selective advantage under antibiotic treatment in a CF airways environment.
  
  
  METHODS
  To test this hypothesis, the reference strain PAO1 and clonal pairs of CF clinical hypermutable and wild-type P. aeruginosa strains belonging to different genotypes were subjected to competition experiments in vitro and in a mouse model of chronic infection.
  
  
  RESULTS
  Both in vitro and in vivo, under antibiotic selection pressure, clinical hypermutable P. aeruginosa strains and the reference PAO1ΔmutS outcompeted their wild-type strains, promoting P. aeruginosa hypermutable strains in the airways colonization. This advantage for the hypermutable strain did not occur in the absence of antibiotic treatments. Severe histopathological lesions were detected during chronic murine airways infection after antibiotic pressure, indicating that the advantage of the hypermutable population in the lungs may contribute to disease progression.
  
  
  CONCLUSIONS
  Overall, these results showed that P. aeruginosa hypermutability, previously associated with a biological cost, increases colonization potential under selection pressure in a context of CF chronic airways infection and can contribute to lung damage during long-term persistence.
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Alcalá-Franco
authors.forename: Sara
authors.initials: S
authors.lastname: Montanari
authors.forename: Cristina
authors.initials: C
authors.lastname: Cigana
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertoni
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D058491:Bacterial Load; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications; D024881:Drug Resistance, Bacterial; D006801:Humans; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D012141:Respiratory Tract Infections / Q000382:microbiology*; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents