Invasive Escherichia coli are a feature of Crohn's disease

Sasaki, Maiko; Sitaraman, S; Babbin, Brian A.; Gerner‐Smidt, Peter; Ribot, Efrain M.; Garrett, Nancy; Alpern, Joel A; Akyildiz, Adil; Theiss, Arianne L.; Nusrat, Asma; Klapproth, Jan–Michael A.

doi:10.1038/labinvest.3700661

Cited by 208 publications

(180 citation statements)

References 60 publications

(54 reference statements)

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“…Most E. coli strains isolated from the ileal mucosa of CD patients are able to adhere to and invade intestinal epithelial cells (14)(15)(16) and belong to the pathogenic group of adherent invasive E. coli (AIEC) (17). AIEC is highly associated with the ileal mucosa in CD patients (14)(15)(16)(18)(19)(20)(21)(22)(23). CD-associated AIEC cells adhere to the brush border of primary ileal enterocytes isolated from CD patients but not to enterocytes isolated from controls without inflammatory bowel disease.…”

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confidence: 99%

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

et al. 2015

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A critical step in the life cycle of all organisms is the duplication of the genetic material during cell division. Ribonucleotide reductases (RNRs) are essential enzymes for this step because they control the de novo production of the deoxyribonucleotides required for DNA synthesis and repair. Enterobacteriaceae have three functional classes of RNRs (Ia, Ib, and III), which are transcribed from separate operons and encoded by the genes nrdAB, nrdHIEF, and nrdDG, respectively. Here, we investigated the role of RNRs in the virulence of adherent-invasive Escherichia coli (AIEC) isolated from Crohn's disease (CD) patients. Interestingly, the LF82 strain of AIEC harbors four different RNRs (two class Ia, one class Ib, and one class III). Although the E. coli RNR enzymes have been extensively characterized both biochemically and enzymatically, little is known about their roles during bacterial infection. We found that RNR expression was modified in AIEC LF82 bacteria during cell infection, suggesting that RNRs play an important role in AIEC virulence. Knockout of the nrdR and nrdD genes, which encode a transcriptional regulator of RNRs and class III anaerobic RNR, respectively, decreased AIEC LF82's ability to colonize the gut mucosa of transgenic mice that express human CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6). Microarray experiments demonstrated that NrdR plays an indirect role in AIEC virulence by interfering with bacterial motility and chemotaxis. Thus, the development of drugs targeting RNR classes, in particular NrdR and NrdD, could be a promising new strategy to control gut colonization by AIEC bacteria in CD patients.R ibonucleotide reductase (RNR) is an essential enzyme in all living organisms. It catalyzes the reduction of ribonucleotides (nucleoside triphosphates [NTPs]) to their corresponding 2=-deoxyribonucleotides (deoxynucleoside triphosphates [dNTPs]) and therefore plays an essential role in DNA synthesis and repair. Three RNR classes (classes I, II, and III) exist; these classes exhibit different primary structures, subunit cofactor requirements, and quaternary three-dimensional (3D) structures, but they all are allosterically regulated and share similar catalytic mechanisms (1, 2). Class I RNRs are oxygendependent enzymes that occur in eubacteria, eukaryotes, and some viruses. This class comprises two main subgroups (Ia and Ib). Class Ia RNRs are encoded by an operon containing nrdA and nrdB genes. These genes encode the NrdA subunit, which is catalytically and allosterically regulated, and the NrdB subunit, which possesses radical-generating activity. Class Ib RNRs are encoded by an operon containing the nrdH, nrdI, nrdE, and nrdF genes, which encode the corresponding specific redoxin NrdH, the activating subunit NrdI, the catalytic subunit NrdE, and the radical-generating subunit NrdF. Class III RNRs are present in facultative anaerobic and strict anaerobic microorganisms and use S-adenosylmethionine and iron-sulfur clusters in the NrdG accessory protein to create a stab...

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Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

et al. 2015

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“…However, CD-associated E. coli strains, especially the strains from inflamed CD tissue, have been shown to be much more invasive than UC-associated strains, and E. coli strains from inflamed CD tissue induced significantly higher TNF-α expression in macrophage cell lines than UC-associated E. coli strains [38]. CEACAM6 is expressed in the colonic mucosa of patients with CD and UC [8,42], and could be a receptor for colonic E. coli strains that display AIEC-like activity in cultured epithelial cells.…”

Section: The Association Of Adherent and Invasive E Coli With CDmentioning

confidence: 99%

“…While AIEC are generally associated with ileal colonization, invasive AIEC-like E. coli strains have also been isolated from the colonic mucosa of patients with CD, UC and colon cancer [37,38,43]. However, CD-associated E. coli strains, especially the strains from inflamed CD tissue, have been shown to be much more invasive than UC-associated strains, and E. coli strains from inflamed CD tissue induced significantly higher TNF-α expression in macrophage cell lines than UC-associated E. coli strains [38].…”

Section: The Association Of Adherent and Invasive E Coli With CDmentioning

confidence: 99%

“…Culture-based analysis of E. coli isolated from the mucosa of patients with CD has revealed that many strains display pathogenlike behavior in cultured cells [26,[36][37][38]. The best-characterized CD-associated E. coli strain, LF82 (isolated by DarfeuilleMichaud from the ileum of a patient from Lille, France), adheres to, invades, persists and replicates in cultured intestinal epithelial cells [36].…”

Section: The Association Of Adherent and Invasive E Coli With CDmentioning

confidence: 99%

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Microflora in Crohn’s disease: the emergence of adherent and invasiveEscherichia coli

Dogan¹,

Simpson²

2008

Expert Review of Clinical Immunology

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“…16 However, not all of these phenotypically-defined strains (that is, based on invasive capacity) may share all of the same proposed virulence genes. 14,[17][18][19] Although some of the mechanisms by which these bacteria lead to colonization and intestinal injury, such as induction of carcinoembryonic antigen-related celladhesion molecule (CEACAM)-6 receptor expression by TNFα, 20,21 and expression of a unique type of type 1 binding pilus 22 have been described, it is highly likely that and environmental factors that lead to disease development, or whether disease is directly induced when AIEC strains colonize the bowel. Nevertheless, factors that favor their colonization have been identified, including CEACAM receptor overexpression in the gut 20,21 and the capacity of the pathogen to form biofilms.…”

Section: Aiec and The Epithelial Barriermentioning

confidence: 99%

Adherent-invasiveEscherichia colitarget the epithelial barrier

et al. 2010

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I nvolvement of intestinal microbes in the pathogenesis of chronic inflammatory bowel diseases (IBD, includingCrohn disease and ulcerative colitis) is well established. However, the mechanisms by which bacteria lead to intestinal injury in IBD remain unclear and are the focus of current research. Using adherentinvasive Escherichia coli (AIEC) strain LF82, which is linked to Crohn disease, we recently demonstrated the ability of these intestinal microbes to disrupt the integrity of epithelial cells in an in vitro cell model. This disruption provides the bacteria a capacity to penetrate into and beyond the epithelial monolayer, replicate in cells, disseminate within the host, and induce a chronic immune response. These findings provide a link between microbes related to IBD, disruption of the intestinal epithelial cell barrier, and disease pathogenesis.In this addendum, we provide a synopsis on current data concerning the role of AIEC in the pathogenesis of intestinal inflammation, summarise our recent findings, and highlight the central role of the epithelium in mucosal defence. We also discuss, in more detail, the potential implications of our findings and present ideas for future studies and targets for intervention.

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Invasive Escherichia coli are a feature of Crohn's disease

Cited by 208 publications

References 60 publications

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

Microflora in Crohn’s disease: the emergence of adherent and invasiveEscherichia coli

Adherent-invasiveEscherichia colitarget the epithelial barrier

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