title: Pathogen DNA as target for host-generated oxidative stress: role for repair of bacterial DNA damage in Helicobacter pylori colonization.
abstract: Helicobacter pylori elicits an oxidative stress during host colonization. This oxidative stress is known to cause lesions in the host DNA. Here we addressed the question as to whether the pathogen DNA is subject to lethal or mutational damage by the host-generated oxidative response. H. pylori Hpnth mutants unable to repair oxidized pyrimidines from the bacterial DNA were generated. H. pylori strains lacking a functional endonuclease III (HpNth) showed elevated spontaneous and induced mutation rates and were more sensitive than the parental strain to killing by exposure to oxidative agents or activated macrophages. Although under laboratory conditions the Hpnth mutant strain grows as well as the wild-type strain, in a mouse infection the stomach bacterial load gradually decreases while the population in the wild-type strain remains stable, showing that endonuclease III deficiency reduces the colonization capacity of the pathogen. In coinfection experiments with a wild-type strain, Hpnth cells are eradicated 15 days postinfection (p.i.) even when inoculated in a 1:9 wild-type:mutant strain ratio, revealing mutagenic lesions that are counterselected under competition conditions. These results show that the host effectively induces lethal and premutagenic oxidative DNA adducts on the H. pylori genome. The possible consequences of these DNA lesions on the adaptability of H. pylori strains to new hosts are discussed.
authors.affiliation: Département de Radiobiologie et Radiopathologie, Commissariat à l'Energie Atomique (CEA), Unité Mixte de Recherche 217/Centre National de la Recherche Scientifique, BP6, F-92265 Fontenay-aux-Roses, France.
authors.forename: Eyleen J
authors.initials: EJ
authors.lastname: O'Rourke
authors.forename: Catherine
authors.initials: C
authors.lastname: Chevalier
authors.forename: A Viviana
authors.initials: AV
authors.lastname: Pinto
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Thiberge
authors.forename: Luis
authors.initials: L
authors.lastname: Ielpi
authors.forename: Agnès
authors.initials: A
authors.lastname: Labigne
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Radicella
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D005838:Genotype; D016480:Helicobacter pylori / Q000166:cytology / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013270:Stomach / Q000382:microbiology; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D024483:Vitamin K 3; D004247:DNA; D006861:Hydrogen Peroxide; D010100:Oxygen; D012293:Rifampin