Cytolethal Distending Toxin Damages the Oral Epithelium of Gingival Explants

Damek-Poprawa, Monika; Haris, Mohammad; Volgina, Alla; Korostoff, Jonathan; DiRienzo, Joseph M.

doi:10.1177/0022034511403743

Cited by 30 publications

(41 citation statements)

References 28 publications

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“…Although the role of A. actinomycetemcomitans OMVs in periodontal disease has not yet been elucidated, our present data support that OMVs could deliver biologically active CDT and additional virulence factors into susceptible cells of the periodontium. Two recent studies have suggested that in the presence of A. actinomycetemcomitans, CDT toxicity may play a part in the early pathogenesis of periodontitis (14,50). This would be consistent with OMVs promoting damage in the sulcular/junctional epithelium, which remains to be experimentally assessed.…”

Section: Discussionmentioning

confidence: 69%

“…It has been suggested that RANKL activation is the primary factor in acute alveolar bone absorption in aggressive periodontitis (9). Moreover, recent reports have revealed that purified A. actinomycetemcomitans CDT holotoxin caused structural damage to rat and human oral epithelia ex vivo (14). It also induced cell cycle arrest and damage in rat periodontal epithelial cells in vivo (50), which is consistent with CDT playing a part in early pathogenesis of periodontitis in the presence of A. actinomycetemcomitans.…”

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confidence: 56%

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Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

et al. 2012

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Aggregatibacter actinomycetemcomitans is implicated in aggressive forms of periodontitis. Similarly to several other Gramnegative species, this organism produces and excretes a cytolethal distending toxin (CDT), a genotoxin associated with cell distention, G 2 cell cycle arrest, and/or apoptosis in many mammalian cell types. In this study, we have identified A. actinomycetemcomitans outer membrane vesicles (OMVs) as a vehicle for simultaneous delivery of multiple proteins, including CDT, into human cells. The OMV proteins were internalized in both HeLa cells and human gingival fibroblasts (HGF) via a mechanism of OMV fusion with lipid rafts in the plasma membrane. The active toxin unit, CdtB, was localized inside the nucleus of the intoxicated cells, whereas OmpA and proteins detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells had a perinuclear distribution. In accordance with a tight association of CdtB with OMVs, vesicles isolated from A. actinomycetemcomitans strain D7SS (serotype a), in contrast to OMVs from a D7SS cdtABC mutant, induced a cytolethal distending effect on HeLa and HGF cells, indicating that OMV-associated CDT was biologically active. Association of CDT with OMVs was also observed in A. actinomycetemcomitans isolates belonging to serotypes b and c, indicating that OMV-mediated release of CDT may be conserved in A. actinomycetemcomitans. Although the role of A. actinomycetemcomitans OMVs in periodontal disease has not yet been elucidated, our present data suggest that OMVs could deliver biologically active CDT and additional virulence factors into susceptible cells of the periodontium.

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Section: Discussionmentioning

confidence: 69%

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confidence: 56%

Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

et al. 2012

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“…However, epithelial cell damage occurred only in rats treated with wild-type Cdt (Ohara et al, 2011). Damaging effects of wild-type A. actinomycetemcomitans Cdt on gingival epithelia were also detected in rat and human gingival explants (Damek-Poprawa et al, 2011, 2013). …”

Section: Evidence That Cdt Expression Is Critical To Diseasementioning

confidence: 94%

The Cytolethal Distending Toxin Contributes to Microbial Virulence and Disease Pathogenesis by Acting As a Tri-Perditious Toxin

Scuron

Boesze‐Battaglia

Dlakić

et al. 2016

Front. Cell. Infect. Microbiol.

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This review summarizes the current status and recent advances in our understanding of the role that the cytolethal distending toxin (Cdt) plays as a virulence factor in promoting disease by toxin-producing pathogens. A major focus of this review is on the relationship between structure and function of the individual subunits that comprise the AB2 Cdt holotoxin. In particular, we concentrate on the molecular mechanisms that characterize this toxin and which account for the ability of Cdt to intoxicate multiple cell types by utilizing a ubiquitous binding partner on the cell membrane. Furthermore, we propose a paradigm shift for the molecular mode of action by which the active Cdt subunit, CdtB, is able to block a key signaling cascade and thereby lead to outcomes based upon programming and the role of the phosphatidylinositol 3-kinase (PI-3K) in a variety of cells. Based upon the collective Cdt literature, we now propose that Cdt is a unique and potent virulence factor capable of acting as a tri-perditious toxin that impairs host defenses by: (1) disrupting epithelial barriers; (2) suppressing acquired immunity; (3) promoting pro-inflammatory responses. Thus, Cdt plays a key role in facilitating the early stages of infection and the later stages of disease progression by contributing to persistence and impairing host elimination.

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“…Hence, OMVs released by this species likely play a role in periodontal disease by delivering biologically active toxins and additional virulence factors into susceptible cells of the periodontium. It has been suggested that in the presence of A. actinomycetemcomitans, CDT toxicity may play a part in the early pathogenesis of periodontitis (21,22). This would be in accordance with OMVs promoting damage in the sulcular/ junctional epithelium.…”

mentioning

confidence: 91%

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

et al. 2014

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Cytolethal Distending Toxin Damages the Oral Epithelium of Gingival Explants

Cited by 30 publications

References 28 publications

Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

Perinuclear Localization of Internalized Outer Membrane Vesicles Carrying Active Cytolethal Distending Toxin from Aggregatibacter actinomycetemcomitans

The Cytolethal Distending Toxin Contributes to Microbial Virulence and Disease Pathogenesis by Acting As a Tri-Perditious Toxin

Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation

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