Genetic Structure and Distribution of the Colibactin Genomic Island among Members of the Family
            <i>Enterobacteriaceae</i>

Putze, Johannes; Hennequin, Claire; Nougayrède, Jean-Philippe; Zhang, Wenlan; Homburg, Stefan; Karch, Helge; Bringer, Marie-Agnès; Fayolle, Corinne; Carniel, Élisabeth; Rabsch, Wolfgang; Oelschlaeger, Tobias A.; Oswald, Éric; Forestier, Christiane; Hacker, Jörg; Dobrindt, Ulrich

doi:10.1128/iai.00522-09

Cited by 268 publications

(293 citation statements)

References 40 publications

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“…E. coli strains belonging to phylogenetic group B2 seem to have a superior capacity to colonize and persist in the colonic microbiota (3), and during the last decade the incidence of B2 strains has risen quickly in colonic microflora of human beings living in high-income countries (2). Surveys have shown that the pks island is present in up to 34% of commensal isolates of phylogenetic group B2 from healthy individuals (4)(5)(6). A recent comparative metagenomic analysis of fecal samples from 13 healthy individuals of various ages, including unweaned infants, showed that pks island genes are found in 40% of samples, especially in infants (32).…”

Section: Discussionmentioning

confidence: 99%

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Cuevas-Ramos

Petit

Marcq

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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667

593

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Escherichia coli is a normal inhabitant of the human gut. However, E. coli strains of phylogenetic group B2 harbor a genomic island called "pks" that codes for the production of a polyketide-peptide genotoxin, Colibactin. Here we report that in vivo infection with E. coli harboring the pks island, but not with a pks isogenic mutant, induced the formation of phosphorylated H2AX foci in mouse enterocytes. We show that a single, short exposure of cultured mammalian epithelial cells to live pks + E. coli at low infectious doses induced a transient DNA damage response followed by cell division with signs of incomplete DNA repair, leading to anaphase bridges and chromosome aberrations. Micronuclei, aneuploidy, ring chromosomes, and anaphase bridges persisted in dividing cells up to 21 d after infection, indicating occurrence of breakage-fusion-bridge cycles and chromosomal instability. Exposed cells exhibited a significant increase in gene mutation frequency and anchorage-independent colony formation, demonstrating the infection mutagenic and transforming potential. Therefore, colon colonization with these E. coli strains harboring the pks island could contribute to the development of sporadic colorectal cancer.T he dense bacterial consortium, called "microbiota," that inhabits the intestinal tract is recognized increasingly as playing a major role in human health and disease. The microbiota generally influences the host in a beneficial fashion by shaping gastrointestinal and immune functions, exerting protection against pathogens, and contributing to metabolic pathways (1). Escherichia coli is a consistent member of the human intestinal microbiota, colonizing the intestine within a few days after birth and persisting throughout the life of the host. The E. coli strain population can be categorized in at least four major phylogenetic groups (A, B1, B2, and D), each group being more specifically associated with certain ecological niches. E. coli strains belonging to group B2 are recovered from the environment less frequently but can persist longer in the colon than other groups and represent 30-50% of strains isolated from the feces of healthy humans living in high-income countries (2, 3). We recently discovered that up to 34% of commensal E. coli strains of the phylogenetic group B2 carry a conserved genomic island named "pks island" (4-6). This gene cluster codes for nonribosomal peptide synthetases (NRPS) and polyketide synthetases (PKS) that allow production of a putative hybrid peptide-polyketide genotoxin, Colibactin. In vitro infection with these strains induces DNA double-strand breaks (DSBs) in cultivated human cells, but the pks island was not proved to cause DNA damage in vivo (4).In this study, we wished to explore whether those bacteria were able to induce genetic damage in vivo on the colonic mucosa and to characterize the consequences of this damage on mammalian cells in relation with the number of infecting bacteria. We report that pks + E. coli induced DSBs in vivo. In addition, infection of various ma...

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Section: Discussionmentioning

confidence: 99%

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Cuevas-Ramos

Petit

Marcq

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

667

593

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“…We note with interest that the genetic context for insertion of the tilivalline gene cluster in the enterobacterial core genome is equivalent to the asnW tRNA locus occupied by the polyketide synthase (pks) genotoxic island in E. coli and some isolates of Klebsiella pneumonia (32,42). The pks locus is highly conserved in the E. coli B2 phylogenetic group and an estimated 21% of humans carry colibactin-synthesizing E. coli in their intestinal microbiota (46).…”

Section: Discussionmentioning

confidence: 99%

“…1D). Comparison with other enterobacterial genomes revealed the location of the gene cluster to be a high-plasticity locus in the core genome typically harboring mobile DNA elements such as the polyketide synthase (pks) genotoxic island of Escherichia coli and determinants for the siderophore system yersiniabactin (29)(30)(31)(32). This genetic context implies that the toxin biosynthesis genes are part of a larger pathogenicity island (PAI).…”

Section: Significancementioning

confidence: 99%

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Schneditz

Rentner

Roier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

180

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Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an animal model. Tilivalline induced apoptosis in cultured human cells in vitro and disrupted epithelial barrier function, consistent with the mucosal damage associated with colitis observed in human AAHC and the corresponding animal model. Our findings reveal the presence of pyrrolobenzodiazepines in the intestinal microbiota and provide a mechanism for colitis caused by a resident pathobiont. The data link pyrrolobenzodiazepines to human disease and identify tilivalline as a target for diagnosis and neutralizing strategies in prevention and treatment of colitis.bacteria | enteric microbiota | cytotoxin

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“…A functional pks island generating DSBS has been identified in the genomes of enterobacteria other than E. coli, such as Citrobacter koseri, Enterobacter aerogenes and Klebsiella pneumoniae [24,25]. Mice infected with K. pneumonia pks+ shows DSBs within 1 to 2 days in liver parenchymal cells only in the presence of colibactin [24].…”

Section: Escherichia Coli Genotoxin Colibactinmentioning

confidence: 99%

“…Mice infected with K. pneumonia pks+ shows DSBs within 1 to 2 days in liver parenchymal cells only in the presence of colibactin [24]. In Taiwanese populations, K. pneumoniae is the most predominant pathogen associated with pyogenic liver abscess, an infection suspected to increase the risk of colorectal cancer development [25].…”

Section: Escherichia Coli Genotoxin Colibactinmentioning

confidence: 99%

When our genome is targeted by pathogenic bacteria

Lemercier

2015

Cell. Mol. Life Sci.

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Eukaryotic cells repair thousands of lesions arising in the genome at each cell cycle. The most hazardous damage is likely DNA doublestrand breaks (DSB) that cleave the double helix backbone. DSBs occur naturally during T-cell receptor and immunoglobulin gene recombination in lymphocytes. DSBs can also arise as a consequence of exogenous stresses (e.g. ionizing irradiation, chemotherapeutic drugs, viruses) or oxidative processes. An increasing number of studies have reported that infection with pathogenic bacteria also alters the host genome, producing DSB and other modifications on DNA. This review focuses on recent data on bacteria-induced DNA damage and the known strategies used by these pathogens to maintain a physiological niche in the host. Even after DNA repair in infected cells, "scars" often remain on chromosomes and might generate genomic instability at the next cell division. Chronic inflammation in tissue, combined with infection and DNA damage, can give rise to genomic instability and eventually cancer. A functional link between the DNA damage response and the innate immune response has been recently established. Pathogenic bacteria also highjack the host cell cycle, often acting on the stability of the master regulator p53, or dampen the DNA damage response to support bacterial replication in an appropriate reservoir. Except in a few cases, the molecular mechanisms responsible for DNA lesions are poorly understood, although ROS release during infection is a serious candidate for generating DNA breaks. Thus, chronic or repetitive infections with genotoxic bacteria represent a common source of DNA lesions that compromise host genome integrity.

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Genetic Structure and Distribution of the Colibactin Genomic Island among Members of the Family Enterobacteriaceae

Cited by 268 publications

References 40 publications

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

When our genome is targeted by pathogenic bacteria

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