title: Biological cost of hypermutation in Pseudomonas aeruginosa strains from patients with cystic fibrosis.
abstract: The high prevalence of hypermutable (mismatch repair-deficient) Pseudomonas aeruginosa strains in patients with cystic fibrosis (CF) is thought to be driven by their co-selection with adaptive mutations required for long-term persistence. Whether the increased mutation rate of naturally hypermutable strains is associated with a biological benefit or cost for the colonization of secondary environments is not known. Thirty-nine P. aeruginosa strains were collected from ten patients with CF during their course of chronic lung infections and screened for hypermutability. Seven hypermutable P. aeruginosa strains (18 %) isolated from six patients with CF (60 %) were identified and assigned to five different genotypes. Complementation and sequence analysis in the mutS, mutL and uvrD genes of these hypermutable P. aeruginosa strains revealed novel mutations. To understand the consequences of hypermutation for the fitness of the organisms, five pairs of clinical wild-type/hypermutable, clonally related P. aeruginosa strains and the laboratory strains PAO1/PAO1DeltamutS were subjected to competition in vitro and in the agar-beads mouse model of chronic airway infection. When tested in competition assay in vitro, the wild-type outcompeted four clinical hypermutable strains and the PAO1DeltamutS strain. In vivo, all of the hypermutable strains were less efficient at establishing lung infection than their wild-type clones. These results suggest that P. aeruginosa hypermutation is associated with a biological cost, reducing the potential for colonization of new environments and therefore strain transmissibility.
authors.affiliation: Institute for Experimental Treatment of Cystic Fibrosis, Scientific Institute H. S. Raffaele, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Montanari
authors.affiliation: Servicio de Microbiologìa Hospital Son Dureta, Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.affiliation: Institute for Experimental Treatment of Cystic Fibrosis, Scientific Institute H. S. Raffaele, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Salerno
authors.affiliation: Servicio de Microbiologìa Hospital Son Dureta, Palma de Mallorca, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mena
authors.affiliation: Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertoni
authors.affiliation: Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
authors.affiliation: Ospedale Maggiore Policlinico, CF Clinic, Milano, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cariani
authors.affiliation: Institute for Experimental Treatment of Cystic Fibrosis, Scientific Institute H. S. Raffaele, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Conese
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.affiliation: Institute for Experimental Treatment of Cystic Fibrosis, Scientific Institute H. S. Raffaele, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000382:microbiology*; D053843:DNA Mismatch Repair; D004195:Disease Models, Animal; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D017422:Sequence Analysis, DNA; D014774:Virulence
chemical_list: D051719:MutS DNA Mismatch-Binding Protein