Breaking the Gingival Epithelial Barrier: Role of the Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin in Oral Infectious Disease - PubMed (original) (raw)

Breaking the Gingival Epithelial Barrier: Role of the Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin in Oral Infectious Disease

Joseph M DiRienzo. Cells. 2014.

Abstract

The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is part of the HACEK group that causes infective endocarditis, a constituent of the oral flora that promotes some forms of periodontal disease and a member of the family of species that secrete a cytolethal distending toxin (Cdt). The family of bacteria that express the cdt genes participate in diseases that involve the disruption of a mucosal or epithelial layer. In vitro studies have shown that human gingival epithelial cells (HGEC) are native targets of the Cdt that typically induces DNA damage that signals growth arrest at the G2/M interphase of the cell cycle. The gingival epithelium is an early line of defense in the oral cavity against microbial assault. When damaged, bacteria collectively gain entry into the underlying connective tissue where microbial products can affect processes and pathways in infiltrating inflammatory cells culminating in the destruction of the attachment apparatus of the tooth. One approach has been the use of an ex vivo gingival explant model to assess the effects of the Cdt on the morphology and integrity of the tissue. The goal of this review is to provide an overview of these studies and to critically examine the potential contribution of the Cdt to the breakdown of the protective gingival barrier.

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Figures

Figure 1

Figure 1

Computer model of the _Aa_Cdt showing the structural relationship of the three subunits: CdtA, CdtB and CdtC. The subunits are depicted as ribbon backbone models using the Protein Data Bank (PDB) file 2F2F, deposited by Yamada et al. [29], and UCSF Chimera 1.8.1. Side chains are shown only in CdtB. The surfaces of CdtA and CdtC are shown as mesh models. Two residues, H160 and H274, in the active site of CdtB are required for toxin activity. Abbreviations: Cdt, cytolethal distending toxin.

Figure 2

Figure 2

Rooted phylogenetic tree of the deduced amino acid sequences of a representative group of deoxyribonucleases (DNase I), inositol polyphosphate 5-phosphatases and sphingomyelinase. The tree was constructed with PHYLIP 3.6. The lengths of the lines show relative genetic distances.

Figure 3

Figure 3

Checkpoint pathway, in response to DNA damage, that leads to growth arrest at the G2/M interphase of the cell cycle in epithelioid cells. The inset illustrates the standard DNA damage checkpoints at G1/S and G2/M in the cell cycle. Cell cycle arrest at G2/M can be measured by flow cytometry or cell sorting. Populations that are arrested at G2/M accumulate cells that have a 4_n_ DNA content.

Figure 4

Figure 4

Human gingival explant (HGX) model of the effects of secreted _Aa_Cdt on tissue obtained from clinically healthy subjects. HGX were untreated or exposed to recombinant wild-type _Aa_Cdt (CdtABC) or native toxin secreted by the bacterium (Cdtsec). Tissue sections were stained with hematoxylin and eosin. Abbreviations: KL, keratinized layer; SL, spinous layer; RP, rete peg; CT, connective tissue. Inset shows the overall histology of the gingival tissues and various types of epithelium (junctional, sulcular and oral) in the upper jaw of a rat. The tissue was decalcified, sectioned and stained with hematoxylin and eosin.

Figure 5

Figure 5

Model of the effects of the _Aa_Cdt on gingival epithelial cell adherens junctions in situ. E-cadherin was detected with a polyclonal antibody conjugated to fluorescein (red fluorescence) in untreated HGX and explants exposed to recombinant _Aa_Cdt. Cell nuclei were stained with DAPI (blue fluorescence). Abbreviations: SL, spinous layer; RP, rete peg; CT, connective tissue.

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References

    1. Norskov-Lauritsen N., Kilian M. Reclassification of Actinobacillus actinomycetemcomitans, Haemophilus aphrophilus, Haemophilus paraphrophilus; Haemophilus segnis as Aggregatibacter actinomycetemcomitans gen. nov., comb. nov., Aggregatibacter aphrophilus comb. nov. and Aggregatibacter segnis comb. nov., and emended description of Aggregatibacter aphrophilus to include V factor-dependent and V factor-independent isolates. Int. J. Syst. Evol. Microbiol. 2006;56:2135–2146. doi: 10.1099/ijs.0.64207-0. - DOI - PubMed
    1. Feder H.M.J., Roberts J.C., Salazar J., Leopold H.B., Toro-Salazar O. HACEK endocarditis in infants and children: Two cases and a literature review. Pediatr. Infect. Dis. J. 2003;22:557–562. - PubMed
    1. Armitage G.C. Comparison of the microbiological features of chronic and aggressive periodontitis. Periodontology. 2010;53:70–88. doi: 10.1111/j.1600-0757.2010.00357.x. - DOI - PubMed
    1. Darveau R.P. Periodontitis: A polymicrobial disruption of host homeostasis. Nat. Rev. Microbiol. 2010;8:481–490. doi: 10.1038/nrmicro2337. - DOI - PubMed
    1. Taubman M.A., Valverde P., Han X., Kawai T. Immune response: The key to bone resorption in periodontal disease. J. Periodontol. 2005;76:2033–2041. doi: 10.1902/jop.2005.76.11-S.2033. - DOI - PubMed

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