Cytotoxic Escherichia coli strains encoding colibactin colonize laboratory mice

García, Alexis; Mannion, Anthony; Feng, Yan; Madden, Carolyn M.; Bakthavatchalu, Vasudevan; Shen, Zeli; Ge, Zhongming; Fox, James G.

doi:10.1016/j.micinf.2016.07.005

Cited by 17 publications

(29 citation statements)

References 48 publications

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“…Thus it might be expected that IL-22 driven iNOS induction could lead to expansion of Enterobacteriaceae including those that carry genotoxins associated with cancer. In fact, we have observed the widespread presence of Colibactin producin E. coli within our colony 37 , and although not specifically quantified in this study, it is possible that Hh could promote DNA damage by enhancing colonization with these E. coli . The relationship between Hh-infection, dysbiosis, genotoxins, and DNA damage will clearly require further studies.…”

Section: Discussionmentioning

confidence: 66%

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

et al. 2017

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The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh-infection induces DNA damage in this model and whether this depends on NO has not been determined. Here, we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22 dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.

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Section: Discussionmentioning

confidence: 66%

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

et al. 2017

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“…The promotion effect was dependent on expression of the pks island [ 15 ]. In a previous study from our laboratory, 88% of E. coli isolates from laboratory mice encoded pks genes and belonged to phylogenetic group B2 [ 16 ]. Our findings indicated that colibactin-encoding E. coli commonly colonize laboratory mice and may induce clinical and subclinical disease that may impact in vivo experimental results [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Escherichia coli strains encoding colibactin and cytotoxic necrotizing factor (CNF) colonize laboratory macaques

et al. 2017

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BackgroundMany Escherichia coli strains are considered to be a component of the normal flora found in the human and animal intestinal tracts. While most E. coli strains are commensal, some strains encode virulence factors that enable the bacteria to cause intestinal and extra-intestinal clinically-relevant infections. Colibactin, encoded by a genomic island (pks island), and cytotoxic necrotizing factor (CNF), encoded by the cnf gene, are genotoxic and can modulate cellular differentiation, apoptosis and proliferation. Some commensal and pathogenic pks+ and cnf+ E. coli strains have been associated with inflammation and cancer in humans and animals.ResultsIn the present study, E. coli strains encoding colibactin and CNF were identified in macaque samples. We performed bacterial cultures utilizing rectal swabs and extra-intestinal samples from clinically normal macaques. A total of 239 E. coli strains were isolated from 266 macaques. The strains were identified biochemically and selected isolates were serotyped as O88:H4, O25:H4, O7:H7, OM:H14, and OM:H16. Specific PCR for pks and cnf1 gene amplification, and phylogenetic group identification were performed on all E. coli strains. Among the 239 isolates, 41 (17.2%) were pks+/cnf1−, 19 (7.9%) were pks−/cnf1+, and 31 (13.0%) were pks+/cnf1+. One hundred forty-eight (61.9%) E. coli isolates were negative for both genes (pks−/cnf1−). In total, 72 (30.1%) were positive for pks genes, and 50 (20.9%) were positive for cnf1. No cnf2+ isolates were detected. Both pks+ and cnf1+ E. coli strains belonged mainly to phylogenetic group B2, including B21. Colibactin and CNF cytotoxic activities were observed using a HeLa cell cytotoxicity assay in representative isolates. Whole genome sequencing of 10 representative E. coli strains confirmed the presence of virulence factors and antibiotic resistance genes in rhesus macaque E. coli isolates.ConclusionsOur findings indicate that colibactin- and CNF-encoding E. coli colonize laboratory macaques and can potentially cause clinical and subclinical diseases that impact macaque models.Electronic supplementary materialThe online version of this article (10.1186/s13099-017-0220-y) contains supplementary material, which is available to authorized users.

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“…In this report, we announce the draft genomes of five novel B2-phylotype E. coli strains isolated from the feces of two asymptomatic surveillance mice, the uterine fluid of a transgenic mouse, and from the blood of two experimental immunocompromised mice with sepsis housed under specific-pathogen-free conditions. We previously found all these strains except A4 were PCR-positive for the PKS genes clbA and clbQ and caused megalocytosis and γ-H2AX-detectable DNA damage in HeLa cells in vitro , suggesting colibactin activity by these organisms ([ 7 ]; our unpublished data). We briefly describe the features of these novel E. coli genomes in context to the previously sequenced genomes of NC101 and the PKS-containing septicemia- and meningitis-causing strains IHE3034 and A192PP ( 4 , 6 ).…”

Section: Genome Announcementmentioning

confidence: 89%

Draft Genome Sequences of Five Novel Polyketide Synthetase-Containing Mouse Escherichia coli Strains

et al. 2016

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Cytotoxic Escherichia coli strains encoding colibactin colonize laboratory mice

Cited by 17 publications

References 48 publications

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

Cytotoxic Escherichia coli strains encoding colibactin and cytotoxic necrotizing factor (CNF) colonize laboratory macaques

Draft Genome Sequences of Five Novel Polyketide Synthetase-Containing Mouse Escherichia coli Strains

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