Detection of cytolethal distending toxin activity and <i>cdt</i> genes in <i>Actinobacillus actinomycetemcomitans</i> isolates from geographically diverse populations

Fabris, A.; DiRienzo, Joseph M.; Wikström, M.; Mayer, Márcia Pinto Alves

doi:10.1034/j.1399-302x.2002.170405.x

Cited by 55 publications

(50 citation statements)

References 38 publications

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“…mRNA levels of cdt were low in serotype a reference strain at the control condition (Table 3), supporting our previous finding that this strain is not as cytotoxic as JP2 (6, 27). However, cdtB was upregulated after prolonged cell exposure in the serotype a strain, suggesting that it may be able to produce high levels of CDT under certain conditions.…”

Section: Discussionsupporting

confidence: 87%

Differential transcription of virulence genes in Aggregatibacter actinomycetemcomitans serotypes

Umeda

Longo

Simionato

et al. 2013

Journal of Oral Microbiology

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Background Aggregatibacter actinomycetemcomitans serotypes are clearly associated with periodontitis or health, which suggests distinct strategies for survival within the host.ObjectiveWe investigated the transcription profile of virulence-associated genes in A. actinomycetemcomitans serotype b (JP2 and SUNY 465) strains associated with disease and serotype a (ATCC 29523) strain associated with health.DesignBacteria were co-cultured with immortalized gingival epithelial cells (OBA-9). The adhesion efficiency after 2 hours and the relative transcription of 13 genes were evaluated after 2 and 24 hours of interaction.ResultsAll strains were able to adhere to OBA-9, and this contact induced transcription of pgA for polysaccharide biosynthesis in all tested strains. Genes encoding virulence factors as Omp29, Omp100, leukotoxin, and CagE (apoptotic protein) were more transcribed by serotype b strains than by serotype a. ltxA and omp29, encoding the leukotoxin and the highly antigenic Omp29, were induced in serotype b by interaction with epithelial cells. Factors related to colonization (aae, flp, apaH, and pgA) and cdtB were upregulated in serotype a strain after prolonged interaction with OBA-9.ConclusionGenes relevant for surface colonization and interaction with the immune system are regulated differently among the strains, which may help explaining their differences in association with disease.

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Section: Discussionsupporting

confidence: 87%

Differential transcription of virulence genes in Aggregatibacter actinomycetemcomitans serotypes

Umeda

Longo

Simionato

et al. 2013

Journal of Oral Microbiology

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“…actinomycetemcomitans is the only oral bacterial species known to produce CDT (70). A number of studies collectively support that CDT may be important in the pathogenesis of aggressive periodontitis (1,19,64), although the actual contribution of CDT to this disease is not yet understood. In vitro studies have revealed that CDT stimulated receptor activator of NF-B ligand (RANKL) in human gingival fibroblasts (HGF) (9), which comprise the major cell population of the gingival connective tissue (5).…”

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confidence: 99%

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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“…A majority (39/40) of clinical isolates from Brazil, Kenya, Japan and Sweden were also found to harbor the cdt genes and produce the AaCDT (Fabris et al 2002). Although there was some variation in toxin production among the strains, no clear relationship between CDT activity and periodontal status could be found.…”

Section: Occurrence Of Cdts In Clinical Isolates From Various Geograpmentioning

confidence: 87%

Cytolethal distending toxins

Thelestam

Reviews of Physiology, Biochemistry and Pharmacology

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The cytolethal distending toxins (CDTs) constitute the most recently discovered family of bacterial protein toxins. CDTs are unique among bacterial toxins as they have the ability to induce DNA double strand breaks (DSBs) in both proliferating and nonproliferating cells, thereby causing irreversible cell cycle arrest or death of the target cells. CDTs are encoded by three linked genes ( cdtA, cdtB and cdtC) which have been identified among a variety of Gram-negative pathogenic bacteria. All three of these gene products are required to constitute the fully active holotoxin, and this is in agreement with the recently determined crystal structure of CDT. The CdtB component has functional homology with mammalian deoxyribonuclease I (DNase I). Mutation of the conserved sites necessary for this catalytic activity prevents the induction of DSBs as well as all subsequent intoxication responses of target cells. CDT is endocytosed via clathrin-coated pits and requires an intact Golgi complex to exert the cytotoxic activity. Several issues remain to be elucidated regarding CDT biology, such as the detailed function(s) of the CdtA and CdtC subunits, the identity of the cell surface receptor(s) for CDT, the final steps in the cellular internalization pathway, and a molecular understanding of how CDT interacts with DNA. Moreover, the role of CDTs in the pathogenesis of diseases still remains unclear.

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Detection of cytolethal distending toxin activity and cdt genes in Actinobacillus actinomycetemcomitans isolates from geographically diverse populations

Cited by 55 publications

References 38 publications

Differential transcription of virulence genes in Aggregatibacter actinomycetemcomitans serotypes

Differential transcription of virulence genes in Aggregatibacter actinomycetemcomitans serotypes

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

Cytolethal distending toxins

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