Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis

Song, Ming; Park, Yoonsuk; Hasegawa, Yoshinori; Tribble, Gena D.; James, Chloë E.; Handfield, Martin; Stavropoulos, Mary F.; Yılmaz, Özlem; Lamont, Richard J.

doi:10.1111/j.1462-5822.2007.00931.x

Cited by 201 publications

(213 citation statements)

References 69 publications

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“…The organism is intensely invasive, and high numbers of P. gingivalis cells rapidly accumulate in the perinuclear area of gingival epithelial cells (GECs) (2). Both host and internalized bacterial cells remain viable, and indeed, P. gingivalis can suppresses host cell apoptosis through modulation of intrinsic apoptotic pathways (44). In addition to the oral habitat, P. gingivalis can also spread systemically and locate in heart and gestational tissues (32,41), bone (67), and cerebrospinal fluid (25).…”

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Role of the Clp System in Stress Tolerance, Biofilm Formation, and Intracellular Invasion inPorphyromonas gingivalis

et al. 2008

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Clp proteases and chaperones are ubiquitous among prokaryotes and eukaryotes, and in many pathogenic bacteria the Clp stress response system is also involved in regulation of virulence properties. In this study, the roles of ClpB, ClpC, and ClpXP in stress resistance, homotypic and heterotypic biofilm formation, and intracellular invasion in the oral opportunistic pathogen Porphyromonas gingivalis were investigated. Absence of ClpC and ClpXP, but not ClpB, resulted in diminished tolerance to high temperatures. Response to oxidative stress was not affected by the loss of any of the Clp proteins. The clpC and clpXP mutants demonstrated elevated monospecies biofilm formation, and the absence of ClpXP also enhanced heterotypic P. gingivalis-Streptococcus gordonii biofilm formation. All clp mutants adhered to gingival epithelial cells to the same level as the wild type; however, ClpC and ClpXP were found to be necessary for entry into host epithelial cells. ClpB did not play a role in entry but was required for intracellular replication and survival. ClpXP negatively regulated the surface exposure of the minor fimbrial (Mfa) protein subunit of P. gingivalis, which stimulates biofilm formation but interferes with epithelial cell entry. Collectively, these results show that the Clp protease complex and chaperones control several processes that are important for the colonization and survival of P. gingivalis in the oral cavity.

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Role of the Clp System in Stress Tolerance, Biofilm Formation, and Intracellular Invasion inPorphyromonas gingivalis

et al. 2008

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“…Recent investigations have shown that P. gingivalis can accelerate the cell cycle of gingival epithelial cells (GECs) (18), reduce the apoptosis of GECs (19)(20)(21), and enhance the proliferation of immortalized human gingival epithelial cells (IGECs) (17). However, the effect of the individual stages of the host cell cycle on interactions with P. gingivalis has not been previously investigated.…”

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The Periodontal Pathogen Porphyromonas gingivalis Preferentially Interacts with Oral Epithelial Cells in S Phase of the Cell Cycle

2016

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Porphyromonas gingivalis, a key periodontal pathogen, is capable of invading a variety of cells, including oral keratinocytes, by exploiting host cell receptors, including alpha-5 beta-1 (␣5␤1) integrin. Previous studies have shown that P. gingivalis accelerates the cell cycle and prevents apoptosis of host cells, but it is not known whether the cell cycle phases influence bacterium-cell interactions. The cell cycle distribution of oral keratinocytes was characterized by flow cytometry and BrdU (5-bromo-2-deoxyuridine) staining following synchronization of cultures by serum starvation. The effect of cell cycle phases on P. gingivalis invasion was measured by using antibiotic protection assays and flow cytometry, and these results were correlated with gene and surface expression levels of ␣5 integrin and urokinase plasminogen activator receptor (uPAR). There was a positive correlation (R ‫؍‬ 0.98) between the number of cells in S phase and P. gingivalis invasion, the organism was more highly associated with cells in S phase than with cells in G 2 and G 1 phases, and S-phase cells contained 10 times more bacteria than did cells that were not in S phase. Our findings also show that ␣5 integrin, but not uPAR, was positively correlated with cells in S phase, which is consistent with previous reports indicating that P. gingivalis invasion of cells is mediated by ␣5 integrin. This study shows for the first time that P. gingivalis preferentially associates with and invades cells in the S phase of the cell cycle. The mechanism of targeting stable dividing cells may have implications for the treatment of periodontal diseases and may partly explain the persistence of this organism at subgingival sites. Porphyromonas gingivalis, a Gram-negative anaerobic bacillus, is one of the major putative periodontal pathogens associated with the initiation and progression of chronic periodontal diseases (1). P. gingivalis has the ability to invade a variety of host cells, including oral keratinocytes (2), through numerous surface-associated virulence factors such as fimbriae (3), hemagglutinins (4), and gingipain proteases (5). The invasion strategy provides a considerable value for bacterium survival, as it could protect periodontal pathogens from host defense mechanisms and assist in their persistence within a site of infection, leading to continuous periodontal inflammation. P. gingivalis has the ability to invade gingival epithelial cells, reside in the cell cytoplasm, remain viable, replicate, and then spread to neighboring epithelial cells (6). However, not all epithelial cells in a population are invaded equally, suggesting that there may be differences between cells in their susceptibility to P. gingivalis invasion, but the reason for this is unclear.Host-bacterium interactions play a dynamic role for the establishment of bacteria within the site of infection. The cohabitation of bacteria with host cells is mediated by several host cell receptors, which facilitate bacterium attachment to host cells and resultant invasion (7). ␣...

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“…It was demonstrated that P. gingivalis transiently activates the JAK1/Stat3 pathways with Akt pathway modulation also being involved. These pathways up-regulate Survivin, at the mRNA level, and ultimately block activation of caspase-3 (122). Considering the many diverse signaling pathways engaged in apoptosis, it is not surprising that some bacteria inhibit or delay apoptosis while others induce it (230).…”

Section: P Gingivalis-induced Resistance To Apoptosismentioning

confidence: 99%

Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis

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Robles-Price²,

McKenzie³

et al. 2008

Front Biosci

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Porphyromonas gingivalis, a major periodontal pathogen, must acquire nutrients from host derived substrates, overcome oxidative stress and subvert the immune system. These activities can be coordinated via the gingipains which represent the most significant virulence factor produced by this organism. In the context of our contribution to this field, we will review the current understanding of gingipain biogenesis, glycosylation, and regulation, as well as discuss their role in oxidative stress resistance and apoptosis. We can postulate a model, in which gingipains may be part of the mechanism for P. gingivalis virulence. KeywordsPorphyromonas gingivalis; gingipains; apoptosis; caspase-independent apoptosis; oxidative stress; VimA; anoikis; N-cadherin; VE-cadherin; integrin β1; VimA; VimE; VimF; DNA repair; glycosylation; virulence; host cell survival; HRgpA; RgpB; Kgp; Review INTRODUCTIONP. gingivalis, a black-pigmented, Gram-negative anaerobe, is an important etiological agent of periodontal disease and is also linked to cardiovascular disease and other systemic diseases [reviewed in (43,103)]. The inflammatory nature of periodontal disease implies that innate host defense mechanisms play a vital role in limiting bacterial growth. During active infection including tissue invasion, toxic reactive oxygen metabolites (e.g. superoxides, hydrogen peroxide and hydroxyl radicals) are mostly generated by polymorphonuclear leukocytes and macrophages (27,29). In order to survive in the inflammatory environment of the periodontal pocket, the bacterium must not only obtain nutrients for growth, but also overcome oxidative stress and subvert the immune defense system. Coordinated regulation of these activities would be beneficial to the bacterium. While there is documented evidence of the response of P. gingivalis to environmental stimulus (56,117,126), one possible mechanism for coordination may occur via the gingipains produced by this bacterium. The presence of P. gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. Protease-associated degradation of cell-cell adhesion proteins on epithelial and endothelial cells resulting in cell death will compromise tissue integrity and facilitate spreading of the bacterium. Furthermore, degradation of the immune response components will facilitate the survival of the organism. Together, these activities may also satisfy the nutritional requirements of the organism. Gingipain-dependent heme accumulation on the bacterium cell surface may also act as an "oxidative sink", thus, leading to protection against oxidative stress (191,193). We will discuss the role of the gingipains in the survival/pathogenicity of P. gingivalis and the unique vim (virulence modulating) locus that is involved in regulation of the gingipains. We will highlight some of our observations that are consistent with the hypothesis that the gingipain...

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Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis

Cited by 201 publications

References 69 publications

Role of the Clp System in Stress Tolerance, Biofilm Formation, and Intracellular Invasion inPorphyromonas gingivalis

Role of the Clp System in Stress Tolerance, Biofilm Formation, and Intracellular Invasion inPorphyromonas gingivalis

The Periodontal Pathogen Porphyromonas gingivalis Preferentially Interacts with Oral Epithelial Cells in S Phase of the Cell Cycle

Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis

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