The
            <i>Bacteroides fragilis</i>
            Pathogenicity Island Is Contained in a Putative Novel Conjugative Transposon

Franco, Augusto A.

doi:10.1128/jb.186.18.6077-6092.2004

Cited by 47 publications

(56 citation statements)

References 47 publications

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“…There is evidence that the enterotoxin pathogenicity island is contained within a novel conjugative transposon (91). This pathogenicity island is flanked by genes encoding mobilization proteins (92) and may thus be transmissible to nontoxigenic strains.…”

Section: The Bad Virulencementioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

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SUMMARY Summary: Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

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Section: The Bad Virulencementioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

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“…A subset of these genetically variable organisms has acquired a novel conjugative transposon (CTn86) containing the B. fragilis pathogenicity island (6). These strains, termed enterotoxigenic B. fragilis (ETBF), are associated with diarrheal disease of animals as well as of children and adults in both developing and industrialized countries (26,34).…”

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The Bacteroides fragilis Toxin Binds to a Specific Intestinal Epithelial Cell Receptor

Shin

Zhang

et al. 2006

Infect Immun

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The Bacteroides fragilis toxin (BFT) is the only known virulence factor of enterotoxigenic B. fragilis. BFT has previously been shown to act, at least in part, through cleavage of the intercellular adhesion protein Ecadherin. A specific cellular receptor for BFT has not been identified. The goal of this study was to determine if the initial interaction of BFT with intestinal epithelial cells was consistent with binding to a specific cellular receptor. Purified BFT was labeled with a fluorophore or iodide to assess specific cellular binding and the properties of BFT cellular binding. BFT binds specifically to intestinal epithelial cell lines in vitro in a polarized manner. However, specific binding occurs only at 37°C and requires BFT metalloprotease activity. The BFT receptor is predicted to be a membrane protein other than E-cadherin or a known protease-activated receptor (PAR1 to PAR4). BFT binding is resistant to acid washing, suggesting an irreversible interaction. Sugar or lipid residues do not appear to be involved in the mechanism of BFT cellular binding, but binding is sensitive to membrane cholesterol depletion. We conclude that intestinal epithelial cells in vitro possess a specific membrane BFT receptor that is distinct from E-cadherin. The data favor a model in which the metalloprotease domain of BFT processes its receptor protein, initiating cellular signal transduction that mediates the biological activity of BFT. However, activation of recognized protease-activated receptors does not mimic or block BFT biological activity or binding, suggesting that additional protease-activated receptors on intestinal epithelial cells remain to be identified.

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“…In this system, the bft-2 gene (from ETBF 86-5443-2-2) and its ϳ700-bp upstream region cloned in plasmid pFD340 (originating pFD340::P-bft) was introduced into pattern III NTBF strains. Pattern III strains (containing conjugative transposon 9343 [CTn9343]-like elements) but not pattern II strains (lacking CTn86-or CTn9343-like elements) (6,8) containing plasmid pFD340::P-bft produced active BFT in quantities that exceed the highly toxigenic wild-type ETBF strain 86-5443-2-2. To evaluate the role of the zinc-binding metalloprotease motif in BFT activity, processing, and secretion, specific amino acid residues of the zinc-binding metalloprotease motif were substituted by nonconservative amino acids in pFD340::P-bft and expressed in pattern III strain NCTC 9343 (13).…”

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Mutation of the Zinc-Binding Metalloprotease Motif AffectsBacteroides fragilisToxin Activity but Does Not Affect Propeptide Processing

et al. 2005

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To evaluate the role of the zinc-binding metalloprotease in Bacteroides fragilis toxin (BFT) processing and activity, the zinc-binding consensus sequences (H348, E349, H352, G355, H358, and M366) were mutated by site-directed-mutagenesis. Our results indicated that single point mutations in the zinc-binding metalloprotease motif do not affect BFT processing but do reduce or eliminate BFT biologic activity in vitro.Enterotoxigenic Bacteroides fragilis (ETBF) strains are strongly linked epidemiologically to diarrheal disease in livestock, young children, and adults (24,25,26,29,30,32,36,40). The only recognized virulence factor of ETBF is a secreted a 20-kDa zinc-dependent metalloprotease termed B. fragilis toxin (BFT) (21). BFT causes fluid accumulation in ligated intestinal loops of lambs, rats, rabbits, and calves (26,27,32). In vitro, BFT alters the morphology of certain human intestinal carcinoma cell lines, particularly HT29/C1 (3,18,33,36). The mechanism of action of BFT is mediated by cleavage of the extracellular domain of the zonula adherens protein, Ecadherin (37). Recently, ETBF strains have also been associated with active inflammatory bowel disease in a small study (28). We and others (15,31,39) have shown that BFT stimulates interleukin-8 (IL-8) secretion by intestinal cells (HT29, T84, and Caco-2) in vitro.Three highly related isotypes of BFT have been identified (termed BFT-1, BFT-2, and BFT-3) (4,5,14,38). All BFTs appear to be structurally similar. BFT is synthesized as a 44-kDa precursor, which is processed to a 20-kDa mature protein (5,17). BFT is predicted to be a member of the metzincin superfamily of zinc-dependent metalloprotease enzymes (21,22). This superfamily contains an elongated zinc-binding metalloprotease motif (HEXXHXXGXXH) and presents a perfectly superimposable methionine residue close to the zincbinding motif. BFT possesses the methionine residue 7 amino acids downstream of the zinc-binding metalloprotease motif, typical of the matrix metalloprotease family (23). The residues of this motif are essential to catalytic activity of the metzincin proteases (23); however, the role of the zinc-binding metalloprotease motif in BFT activity has not been determined.Using vector pFD340 (34), we previously identified an expression system to produce large quantities of active BFT in nontoxigenic B. fragilis (NTBF) strains (7). In this system, the bft-2 gene (from ETBF 86-5443-2-2) and its ϳ700-bp upstream region cloned in plasmid pFD340 (originating pFD340::P-bft) was introduced into pattern III NTBF strains. Pattern III strains (containing conjugative transposon 9343 [CTn9343]-like elements) but not pattern II strains (lacking CTn86-or CTn9343-like elements) (6, 8) containing plasmid pFD340::P-bft produced active BFT in quantities that exceed the highly toxigenic wild-type ETBF strain 86-5443-2-2. To evaluate the role of the zinc-binding metalloprotease motif in BFT activity, processing, and secretion, specific amino acid residues of the zinc-binding metalloprotease motif were substituted ...

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The Bacteroides fragilis Pathogenicity Island Is Contained in a Putative Novel Conjugative Transposon

Cited by 47 publications

References 47 publications

Bacteroides: the Good, the Bad, and the Nitty-Gritty

Bacteroides: the Good, the Bad, and the Nitty-Gritty

The Bacteroides fragilis Toxin Binds to a Specific Intestinal Epithelial Cell Receptor

Mutation of the Zinc-Binding Metalloprotease Motif AffectsBacteroides fragilisToxin Activity but Does Not Affect Propeptide Processing

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