Cytolethal Distending Toxin from Shiga Toxin-Producing
            <i>Escherichia coli</i>
            O157 Causes Irreversible G
            <sub>2</sub>
            /M Arrest, Inhibition of Proliferation, and Death of Human Endothelial Cells

Bielaszewska, Martina; Sinha, Bhanu; Kuczius, Thorsten; Karch, Helge

doi:10.1128/iai.73.1.552-562.2005

Cited by 80 publications

(84 citation statements)

References 62 publications

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“…Increased Rad50 foci and cH2AX are also seen in primary human fibroblasts treated with CjejCDT (Hassane et al, 2003), in primary and established human endothelial cells treated with EcolCdtB-V (Bielaszewska et al, 2005) and cultured human intestinal epithelial H407 cells exposed to HhepCDT (Liyanage et al, 2010). As expected, cH2AX is readily detected in immortalized wild-type human B lymphocyte lines after HducCDT exposure, but it is absent in ATM-defective leukaemic B cell lines obtained from AT patients (Li et al, 2002).…”

Section: ) Nuclear Microinjection Of Purified Recombinantsupporting

confidence: 50%

“…With the exception of a few instances indicating accumulation of phosphorylated Cdk1 (Cdc2) prior to cell cycle arrest, CDT-induced arrest of the cell cycle relies primarily on demonstration of altered patterns of DNA staining with propidium iodide and analysis by florescence-activated cell sorting (Bielaszewska et al, 2005; Comayras et al, 1997; Cortes-Bratti et al, 2001b; Pérès et al, 1997). At least two G2/M checkpoints exist in mammalian cells: an ATM-dependent transient checkpoint which activates in G2 phase cells immediately after DNA damage and a prolonged ATM-independent checkpoint which is activated several hours after damage and reflects accumulation of cells in the G2 phase that were initially damaged during S-phase (Weiss et al, 2003;Xu et al, 2002).…”

Section: Cdt-induced Dna Repair Response and Cell Cycle Arrestmentioning

confidence: 99%

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Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

et al. 2011

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Cytolethal distending toxin (CDT) is a heterotrimeric AB-type genotoxin produced by several clinically important Gram-negative mucocutaneous bacterial pathogens. Irrespective of the bacterial species of origin, CDT causes characteristic and irreversible cell cycle arrest and apoptosis in a broad range of cultured mammalian cell lineages. The active subunit CdtB has structural homology with the phosphodiesterase family of enzymes including mammalian DNase I, and alone is necessary and sufficient to account for cellular toxicity. Indeed, mammalian cells treated with CDT initiate a DNA damage response similar to that elicited by ionizing radiationinduced DNA double strand breaks resulting in cell cycle arrest and apoptosis. The mechanism of CDT-induced apoptosis remains incompletely understood, but appears to involve both p53-dependent and -independent pathways. While epithelial, endothelial and fibroblast cell lines respond to CDT by undergoing arrest of cell cycle progression resulting in nuclear and cytoplasmic distension that precedes apoptotic cell death, cells of haematopoietic origin display rapid apoptosis following a brief period of cell cycle arrest. In this review, the ecology of pathogens producing CDT, the molecular biology of bacterial CDT and the molecular mechanisms of CDT-induced cytotoxicity are critically appraised. Understanding the contribution of a broadly conserved bacterial genotoxin that blocks progression of the mammalian cell cycle, ultimately causing cell death, should assist with elucidating disease mechanisms for these important pathogens. IntroductionJohnson and Lior's seminal observations in the 1980s identified a novel heat-labile toxin in culture filtrates obtained from certain Escherichia coli, Shigella dysenteriae and Campylobacter jejuni strains which caused distinctive and progressive cytoplasmic and nuclear enlargement of cultured mammalian cells, so called cytolethal distending toxin (CDT), and uncovered a novel paradigm amongst bacterial toxins and virulence mechanisms (Johnson & Lior, 1987, 1988a. It was not until many years later that Scott & Kaper (1994) identified the genes encoding CDT in E. coli, which set the stage for fundamental investigations into the ecology, biochemistry and molecular mechanisms of cellular toxicity associated with this novel bacterial toxin (Table 1). While a secreted protein cytotoxin was identified among Haemophilus (Haem.) ducreyi clinical isolates in the early 1990s by Purvén & Lagergård (1992), it was not until the late 1990s that this cytotoxin was conclusively shown to be encoded by a cdt gene cluster with homology to the previously identified E. coli genes (Cope et al., 1997). This discovery extended the range of niches where CDTproducing bacteria are found to include mucocutaneous surfaces of the genital tract in addition to the intestinal tract. At that time, Pérès et al. (1997) first reported that the mechanism of mammalian cell intoxication by E. coli CDT involved arrest of the cell cycle at the G2/M phase. Soon after, these observa...

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Section: ) Nuclear Microinjection Of Purified Recombinantsupporting

confidence: 50%

Section: Cdt-induced Dna Repair Response and Cell Cycle Arrestmentioning

confidence: 99%

Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

et al. 2011

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“…Several previous studies have documented the ability of bacteria to activate endothelial cells (33)(34)(35)(36) and the prominent role that apoptosis plays in the interaction between pathogens and endothelial cells (37)(38)(39). However, there has been little research into the mechanisms involved in injury and protection of the cerebral microcirculation during bacteremia.…”

Section: Discussionmentioning

confidence: 99%

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

Londoño

Carvajal

Strle

et al. 2011

The Journal of Immunology

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IL‐10 deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to brain hemorrhage if they are unable to clear peak bacteremia. Here we investigated the protective role of IL‐10 during relapsing‐remitting bacterial infection and explored the molecular events involved in protection of brain endothelium by IL‐10. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL‐10 deficient mice during relapsing‐remitting infection. Human brain microvascular endothelial cells (HBMEC) upon exposure to whole bacteria or purified bacterial lipoprotein are rapidly killed by apoptosis and produced abundant pro‐inflammatory mediators but did not produce any IL‐10. HBMEC apoptosis during exposure to low number of bacteria was associated with down regulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, exposure to high concentrations of purified outer membrane lipoprotein was associated with dramatic upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL‐10 reversed all the apoptotic signaling changes induced by whole bacteria or purified lipoprotein. The results indicate that IL‐10 prevent brain endothelial cell injury and point to a prominent role for bacterial lipoprotein mediated activation of different apoptosis pathways in this process.

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“…While several E. coli serotypes (1,4,9,15) and toxins (3,19) have been shown to induce apoptosis of epithelial cells, the extent to which ETEC damages host cells is unclear. The prototypic ETEC isolate H10407 was cytotoxic to but failed to induce apoptosis in the macrophage cell line J774 (as measured by DNA fragmentation) (24).…”

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confidence: 99%

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

et al. 2009

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Enterotoxigenic Escherichia coli (ETEC) is a common cause of travelers' and postweaning diarrhea in humans and swine, respectively. The extent to which ETEC damages host cells is unclear. Experiments are presented that probe the ability of porcine ETEC isolates to induce apoptosis and cell death in porcine intestinal epithelial cells. Quantification of host phosphatidylserine exposure following ETEC infection suggested that ETEC induced changes in plasma membrane asymmetry, independent of the expression of the heat-labile enterotoxin. Significant host cell death was not observed. ETEC infection also caused a drastic inhibition of host esterase activity, as measured by calcein fluorescence. While ETEC infection resulted in activation of host caspase 3, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling of DNA double-strand breakage, indicative of late stages of apoptosis, was not observed. Camptothecin-induced apoptosis markedly increased subsequent ETEC adherence. Transfer of cell-free supernatants from apoptotic cells to bacterial inocula prior to infection of naïve cells increased the transcriptional activity of the regulatory region upstream of the K88ac operon and promoted subsequent adherence to host cells.Enterotoxigenic Escherichia coli (ETEC) causes childhood mortality and travelers' diarrhea in humans (36) and postweaning diarrhea in pigs (32). ETEC adherence to intestinal cells is mediated by proteinaceous, species-specific colonization factors (25). ETEC induces water and electrolyte loss from the intestine due to the activities of several enterotoxins, including the heat-labile enterotoxin (LT), the heat-stable toxins (ST), and the enteroaggregative E. coli heat-stable enterotoxin 1 (32).Bacterial pathogens often induce host cell apoptosis to promote their survival and dissemination (16,30). While several E. coli serotypes (1, 4, 9, 15) and toxins (3, 19) have been shown to induce apoptosis of epithelial cells, the extent to which ETEC damages host cells is unclear. The prototypic ETEC isolate H10407 was cytotoxic to but failed to induce apoptosis in the macrophage cell line J774 (as measured by DNA fragmentation) (24). The extent to which LT induces apoptosis has also received considerable attention due to interest in the receptor-binding subunit (LT-B) as a mucosal adjuvant. LT-B induces apoptosis of CD8 ϩ but not CD4 ϩ T cells (37). Some studies indicate that binding of LT-B to GM1 may be sufficient for triggering apoptosis of CD8 ϩ T cells (33), while others suggest that modified LT-B constructs (e.g., H57S) still able to bind GM-1 may fail to trigger apoptosis (14). Yet other studies suggest that LT-mediated apoptosis requires the ADP-ribosylation activity of the LT-A subunit (41).Overall, the roles of ETEC and LT in mediating apoptosis have not been defined clearly and remain somewhat controversial. The goals of this study were therefore to quantify the ability of ETEC to damage porcine intestinal epithelial cells, to clarify the role of LT in these processes, and to me...

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Cytolethal Distending Toxin from Shiga Toxin-Producing Escherichia coli O157 Causes Irreversible G ₂ /M Arrest, Inhibition of Proliferation, and Death of Human Endothelial Cells

Cited by 80 publications

References 62 publications

Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

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Cytolethal Distending Toxin from Shiga Toxin-Producing Escherichia coli O157 Causes Irreversible G 2 /M Arrest, Inhibition of Proliferation, and Death of Human Endothelial Cells

Cited by 80 publications

References 62 publications

Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

EnterotoxigenicEscherichia coliModulates Host Intestinal Cell Membrane Asymmetry and Metabolic Activity

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Product

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Cytolethal Distending Toxin from Shiga Toxin-Producing Escherichia coli O157 Causes Irreversible G ₂ /M Arrest, Inhibition of Proliferation, and Death of Human Endothelial Cells