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1
Waller, Tobias, Laura Kesper, Josefine Hirschfeld, Henrik Dommisch, Johanna Kölpin, Johannes Oldenburg, Julia Uebele, et al. "Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner." Infection and Immunity 84, no. 4 (February 8, 2016): 1194–204. http://dx.doi.org/10.1128/iai.01390-15.
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Porphyromonas gingivalisis an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed fromP. gingivalispromote monocyte unresponsiveness to liveP. gingivalisbut retain reactivity to stimulation with bacterial DNA isolated fromP. gingivalisor AIM2 ligand poly(dA·dT). OMV-mediated tolerance ofP. gingivalisis characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness toP. gingivalis; full reactivity toP. gingivaliscan be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition ofP. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4—and not of TLR2—restores responsiveness toP. gingivalis. Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose thatP. gingivalisOMV contribute to local immune evasion ofP. gingivalisby hampering the host response.
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Huang, George T. J., Daniel Kim, Jonathan K. H. Lee, Howard K. Kuramitsu, and Susan Kinder Haake. "Interleukin-8 and Intercellular Adhesion Molecule 1 Regulation in Oral Epithelial Cells by Selected Periodontal Bacteria: Multiple Effects of Porphyromonas gingivalis via Antagonistic Mechanisms." Infection and Immunity 69, no. 3 (March 1, 2001): 1364–72. http://dx.doi.org/10.1128/iai.69.3.1364-1372.2001.
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ABSTRACT Interaction of bacteria with mucosal surfaces can modulate the production of proinflammatory cytokines and adhesion molecules produced by epithelial cells. Previously, we showed that expression of interleukin-8 (IL-8) and intercellular adhesion molecule 1 (ICAM-1) by gingival epithelial cells increases following interaction with several putative periodontal pathogens. In contrast, expression of IL-8 and ICAM-1 is reduced after Porphyromonas gingivalis ATCC 33277 challenge. In the present study, we investigated the mechanisms that govern the regulation of these two molecules in bacterially infected gingival epithelial cells. Experimental approaches included bacterial stimulation of gingival epithelial cells by either a brief challenge (1.5 to 2 h) or a continuous coculture throughout the incubation period. The kinetics of IL-8 and ICAM-1 expression following brief challenge were such that (i) secretion of IL-8 by gingival epithelial cells reached its peak 2 h following Fusobacterium nucleatum infection whereas it rapidly decreased within 2 h after P. gingivalis infection and remained decreased up to 30 h and (ii) IL-8 and ICAM-1 mRNA levels were up-regulated rapidly 2 to 4 h postinfection and then decreased to basal levels 8 to 20 h after infection with either Actinobacillus actinomycetemcomitans, F. nucleatum, or P. gingivalis. Attenuation of IL-8 secretion was facilitated by adherent P. gingivalis strains. The IL-8 secreted from epithelial cells after F. nucleatum stimulation could be down-regulated by subsequent infection with P. gingivalisor its culture supernatant. Although these results suggested that IL-8 attenuation at the protein level might be associated with P. gingivalis proteases, the Arg- and Lys-gingipain proteases did not appear to be solely responsible for IL-8 attenuation. In addition, while P. gingivalis up-regulated IL-8 mRNA expression, this effect was overridden when the bacteria were continuously cocultured with the epithelial cells. The IL-8 mRNA levels in epithelial cells following sequential challenge with P. gingivalis andF. nucleatum and vice versa were approximately identical and were lower than those following F. nucleatum challenge alone and higher than control levels or those following P. gingivalis challenge alone. Thus, together with the protease effect, P. gingivalis possesses a powerful strategy to ensure the down-regulation of IL-8 and ICAM-1.
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Suzuki, Mitsuo, Toshizo Toyama, Kiyoko Watanabe, Haruka Sasaki, Shuta Sugiyama, Fumihiko Yoshino, Ayaka Yoshida, et al. "Ameliorating Effects of Jixueteng in a Mouse Model of Porphyromonas gingivalis-Induced Periodontitis: Analysis Based on Gingival Microcirculatory System." Natural Product Communications 13, no. 12 (December 2018): 1934578X1801301. http://dx.doi.org/10.1177/1934578x1801301230.
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Jixueteng, the dried stem of Spatholobus suberectus Dunn (Leguminosae), is a traditional Chinese herbal medicine that promotes blood circulation and can be used to treat blood stasis. In this study, we aimed to investigate the potential of Jixueteng as a preventive and therapeutic drug for periodontitis. We investigated the inhibitory effects of Jixueteng on Porphyromonas gingivalis ( P. gingivalis)-induced gingival circulatory disturbances in mice. Seventy-two male C57BL/6N mice (4-week-old) were randomly divided into the following four groups of 12 mice each. Group 1 served as the P. gingivalis noninfected control (control group). Group 2 was administered Jixueteng extract in drinking water to P. gingivalis noninfected control mice. Group 3 was infected orally with P. gingivalis; and group 4 was administered Jixueteng extract in drinking water and then infected with P. gingivalis. To evaluate the effect of Jixueteng on gingival microcirculation systems, we examined gingival blood flow (GBF) in oral microcirculation in vivo in a mouse model of periodontitis. Gingival reactive hyperemia (GRH) was determined using laser Doppler flowmetry. GRH was elicited by the release of occlusive gingival compression by the laser Doppler probe (diameter 1.0 mm) for 1 min. GRH was estimated by basal blood flow, maximum response (Peak), the time taken for the maximum response to fall to one half (T1/2) and increased total amount of blood flow (Mass). Furthermore, to determine the effect of an oral application of P. gingivalis and/or Jixueteng on GBF and gingival microvessel ultrastructure, morphological analysis of gingival microvessels was performed by using a vascular resin cast model. Administration of Jixueteng to P. gingivalis-infected animals significantly reduced GRH, especially T1/2 and Mass, compared to that in P. gingivalis-infected animals. Alternatively, in the morphological analysis, reduction of the gingival capillary network which resulted from P. gingivalis-infection was improved by Jixueteng administration. Since Jixueteng ameliorates P. gingivalis infection-induced gingival circulatory disturbance, it may be useful in the treatment of P. gingivalis-induced periodontitis.
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Griffen, Ann L., Mitzi R. Becker, Sharon R. Lyons, Melvin L. Moeschberger, and Eugene J. Leys. "Prevalence of Porphyromonas gingivalisand Periodontal Health Status." Journal of Clinical Microbiology 36, no. 11 (1998): 3239–42. http://dx.doi.org/10.1128/jcm.36.11.3239-3242.1998.
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Periodontitis is a common, progressive disease that eventually affects the majority of the population. The local destruction of periodontitis is believed to result from a bacterial infection of the gingival sulcus, and several clinical studies have provided evidence to implicate Porphyromonas gingivalis. If P. gingivalis is a periodontal pathogen, it would be expected to be present in most subjects with disease and rarely detected in subjects with good periodontal health. However, in most previous studies, P. gingivalis has not been detected in the majority of subjects with disease, and age-matched, periodontally healthy controls were not included for comparison. The purpose of the study reported here was to compare the prevalence of P. gingivalis in a group with periodontitis to that of a group that is periodontally healthy. A comprehensive sampling strategy and a sensitive PCR assay were used to maximize the likelihood of detection. The target sequence for P. gingivalis-specific amplification was the transcribed spacer region within the ribosomal operon. P. gingivalis was detected in only 25% (46 of 181) of the healthy subjects but was detected in 79% (103 of 130) of the periodontitis group (P < 0.0001). The odds ratio for being infected with P. gingivalis was 11.2 times greater in the periodontitis group than in the healthy group (95% confidence interval, 6.5 to 19.2). These data implicate P. gingivalisin the pathogenesis of periodontitis and suggest that P. gingivalis may not be a normal inhabitant of a periodontally healthy dentition.
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Bao, X., R. Wiehe, H. Dommisch, and A. S. Schaefer. "Entamoeba gingivalis Causes Oral Inflammation and Tissue Destruction." Journal of Dental Research 99, no. 5 (February 5, 2020): 561–67. http://dx.doi.org/10.1177/0022034520901738.
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A metagenomics analysis showed a strongly increased frequency of the protozoan Entamoeba gingivalis in inflamed periodontal pockets, where it contributed the second-most abundant rRNA after human rRNA. This observation and the close biological relationship to Entamoeba histolytica, which causes inflammation and tissue destruction in the colon of predisposed individuals, raised our concern about its putative role in the pathogenesis of periodontitis. Histochemical staining of gingival epithelium inflamed from generalized severe chronic periodontitis visualized the presence of E. gingivalis in conjunction with abundant neutrophils. We showed that on disruption of the epithelial barrier, E. gingivalis invaded gingival tissue, where it moved and fed on host cells. We validated the frequency of E. gingivalis in 158 patients with periodontitis and healthy controls by polymerase chain reaction and microscopy. In the cases, we detected the parasite in 77% of inflamed periodontal sites and 22% of healthy sites; 15% of healthy oral cavities were colonized by E. gingivalis. In primary gingival epithelial cells, we demonstrated by quantitative real-time polymerase chain reaction that infection with E. gingivalis but not with the oral bacterial pathogen Porphyromonas gingivalis strongly upregulated the inflammatory cytokine IL8 (1,900 fold, P = 2 × 10–4) and the epithelial barrier gene MUC21 (8-fold, P = 7 × 10–4). In gingival fibroblasts, we showed upregulation of the collagenase MMP13 (11-fold, P = 3 × 10–4). Direct contact of E. gingivalis to gingival epithelial cells inhibited cell proliferation. We indicated the strong virulence potential of E. gingivalis and showed that the mechanisms of tissue invasion and destruction are similar to the colonic protozoan parasite E. histolytica. In conjunction with abundant colonization of inflamed periodontal sites and the known resistance of Entamoeba species to neutrophils, antimicrobial peptides, and various antibiotics, our results raise the awareness of this protozoan as a potential and, to date, underrated microbial driver of destructive forms of periodontitis.
6
Darveau, Richard P., Carol M. Belton, Robert A. Reife, and Richard J. Lamont. "Local Chemokine Paralysis, a Novel Pathogenic Mechanism for Porphyromonas gingivalis." Infection and Immunity 66, no. 4 (April 1, 1998): 1660–65. http://dx.doi.org/10.1128/iai.66.4.1660-1665.1998.
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ABSTRACT Periodontitis, which is widespread in the adult population, is a persistent bacterial infection associated with Porphyromonas gingivalis. Gingival epithelial cells are among the first cells encountered by both P. gingivalis and commensal oral bacteria. The chemokine interleukin 8 (IL-8), a potent chemoattractant and activator of polymorphonuclear leukocytes, was secreted by gingival epithelial cells in response to components of the normal oral flora. In contrast, P. gingivalis was found to strongly inhibit IL-8 accumulation from gingival epithelial cells. Inhibition was associated with a decrease in mRNA for IL-8. Antagonism of IL-8 accumulation did not occur in KB cells, an epithelial cell line that does not support high levels of intracellular invasion by P. gingivalis. Furthermore, a noninvasive mutant of P. gingivalis was unable to antagonize IL-8 accumulation. Invasion-dependent destruction of the gingival IL-8 chemokine gradient at sites of P. gingivaliscolonization (local chemokine paralysis) will severely impair mucosal defense and represents a novel mechanism for bacterial colonization of host tissue.
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Liu, Chengcheng, Kendall Stocke, Zackary R. Fitzsimonds, Lan Yakoumatos, Daniel P. Miller, and Richard J. Lamont. "A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC." PLOS Pathogens 17, no. 5 (May 20, 2021): e1009598. http://dx.doi.org/10.1371/journal.ppat.1009598.
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Tyrosine phosphatases are often weaponized by bacteria colonizing mucosal barriers to manipulate host cell signal transduction pathways. Porphyromonas gingivalis is a periodontal pathogen and emerging oncopathogen which interferes with gingival epithelial cell proliferation and migration, and induces a partial epithelial mesenchymal transition. P. gingivalis produces two tyrosine phosphatases, and we show here that the low molecular weight tyrosine phosphatase, Ltp1, is secreted within gingival epithelial cells and translocates to the nucleus. An ltp1 mutant of P. gingivalis showed a diminished ability to induce epithelial cell migration and proliferation. Ltp1 was also required for the transcriptional upregulation of Regulator of Growth and Cell Cycle (RGCC), one of the most differentially expressed genes in epithelial cells resulting from P. gingivalis infection. A phosphoarray and siRNA showed that P. gingivalis controlled RGCC expression through Akt, which was activated by phosphorylation on S473. Akt activation is opposed by PTEN, and P. gingivalis decreased the amount of PTEN in epithelial cells. Ectopically expressed Ltp1 bound to PTEN, and reduced phosphorylation of PTEN at Y336 which controls proteasomal degradation. Ltp-1 induced loss of PTEN stability was prevented by chemical inhibition of the proteasome. Knockdown of RGCC suppressed upregulation of Zeb2 and mesenchymal markers by P. gingivalis. RGCC inhibition was also accompanied by a reduction in production of the proinflammatory cytokine IL-6 in response to P. gingivalis. Elevated IL-6 levels can contribute to periodontal destruction, and the ltp1 mutant of P. gingivalis incited less bone loss compared to the parental strain in a murine model of periodontal disease. These results show that P. gingivalis can deliver Ltp1 within gingival epithelial cells, and establish PTEN as the target for Ltp1 phosphatase activity. Disruption of the Akt1/RGCC signaling axis by Ltp1 facilitates P. gingivalis-induced increases in epithelial cell migration, proliferation, EMT and inflammatory cytokine production.
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Okuda, K., and I. Takazoe. "The Role of Bacteroides Gingivalis in Periodontal Disease." Advances in Dental Research 2, no. 2 (November 1988): 260–68. http://dx.doi.org/10.1177/08959374880020021001.
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The microbial flora in adult advanced periodontitis lesions is comprised of Gram-negative rods, with Bacteroides gingivalis as one of the major representatives. This review deals with biological properties of surface antigens, hemagglutinin (attachment factor), and capsular structure of B. gingivalis. Sera containing high IgG antibody levels to B. gingivalis enhanced the complement-mediated bactericidal activity in vitro, although the susceptibility to complement-mediated lysis differed among B. gingivalis strains. The protective effect of immunization against B. gingival is infection was examined in hamsters in which cotton threads had been tied to the gingival margins of the mandibular first molar. Repeated oral topical application of hyper-immune sera against B. gingivalis resulted in effective elimination of the organisms from the periodontal lesions in the experimental animals.
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Zhou, Yun, Maryta Sztukowska, Qian Wang, Hiroaki Inaba, Jan Potempa, David A. Scott, Huizhi Wang, and Richard J. Lamont. "Noncanonical Activation of β-Catenin by Porphyromonas gingivalis." Infection and Immunity 83, no. 8 (June 1, 2015): 3195–203. http://dx.doi.org/10.1128/iai.00302-15.
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Porphyromonas gingivalisis an established pathogen in periodontal disease and an emerging pathogen in serious systemic conditions, including some forms of cancer. We investigated the effect ofP. gingivalison β-catenin signaling, a major pathway in the control of cell proliferation and tumorigenesis. Infection of gingival epithelial cells withP. gingivalisdid not influence the phosphorylation status of β-catenin but resulted in proteolytic processing. The use of mutants deficient in gingipain production, along with gingipain-specific inhibitors, revealed that gingipain proteolytic activity was required for β-catenin processing. The β-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3β were also proteolytically processed byP. gingivalisgingipains. Cell fractionation and Western blotting demonstrated that β-catenin fragments were translocated to the nucleus. The accumulation of β-catenin in the nucleus followingP. gingivalisinfection was confirmed by immunofluorescence microscopy. A luciferase reporter assay showed thatP. gingivalisincreased the activity of the β-catenin-dependent TCF/LEF promoter.P. gingivalisdid not increase Wnt3a mRNA levels, a finding consistent withP. gingivalis-induced proteolytic processing causing the increase in TCF/LEF promoter activity. Thus, our data indicate thatP. gingivaliscan induce the noncanonical activation of β-catenin and disassociation of the β-catenin destruction complex by gingipain-dependent proteolytic processing. β-Catenin activation in epithelial cells byP. gingivalismay contribute to a proliferative phenotype.
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Chin, Yu-Tang, Meng-Ti Hsieh, Chi-Yu Lin, Po-Jan Kuo, Yu-Chen S. H. Yang, Ya-Jung Shih, Hsuan-Yu Lai, et al. "2,3,5,4′-Tetrahydroxystilbene-2-O-β-glucoside Isolated from Polygoni Multiflori Ameliorates the Development of Periodontitis." Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/6953459.
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Periodontitis, a chronic infection by periodontopathic bacteria, induces uncontrolled inflammation, which leads to periodontal tissue destruction. 2,3,5,4′-Tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygoni Multiflori, reportedly has anti-inflammatory properties. In this study, we investigated the mechanisms of THSG on thePorphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. Human gingival fibroblast cells were treated with lipopolysaccharide (LPS) extracted fromP. gingivalisin the presence of resveratrol or THSG to analyze the expression of TNF-α, IL-1β, and IL-6 genes. Increased AMP-activated protein kinase (AMPK) activation and SirT1 expression were induced by THSG. Treatment of THSG decreased the expression of LPS-induced inflammatory cytokines, enhanced AMPK activation, and increased the expression of SirT1. In addition, it suppressed the activation of NF-κB when cells were stimulated withP. gingivalisLPS. The anti-inflammatory effect of THSG and P. Multiflori crude extracts was reproduced in ligature-induced periodontitis animal modeling. In conclusion, THSG inhibited the inflammatory responses ofP. gingivalis-stimulated human gingival fibroblasts and ameliorated ligature-induced periodontitis in animal model.
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Han, Xiaozhe, Xiaoping Lin, Xiaoqian Yu, Jiang Lin, Toshihisa Kawai, Karen B. LaRosa, and Martin A. Taubman. "Porphyromonas gingivalis Infection-Associated Periodontal Bone Resorption Is Dependent on Receptor Activator of NF-κB Ligand." Infection and Immunity 81, no. 5 (February 25, 2013): 1502–9. http://dx.doi.org/10.1128/iai.00043-13.
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ABSTRACTPorphyromonas gingivalisis one of the oral microorganisms associated with human chronic periodontitis. The purpose of this study is to determine the role of the receptor activator of nuclear factor-κB ligand (RANKL) inP. gingivalisinfection-associated periodontal bone resorption. Inbred female Rowett rats were infected orally on four consecutive days (days 0 to 3) with 1 × 109P. gingivalisbacteria (strain ATCC 33277). Separate groups of rats also received an injection of anti-RANKL antibody, osteoprotegerin fusion protein (OPG-Fc), or a control fusion protein (L6-Fc) into gingival papillae in addition toP. gingivalisinfection. Robust serum IgG and salivary IgA antibody (P< 0.01) and T cell proliferation (P< 0.05) responses toP. gingivaliswere detected at day 7 and peaked at day 28 inP. gingivalis-infected rats. Both the concentration of soluble RANKL (sRANKL) in rat gingival tissues (P< 0.01) and periodontal bone resorption (P< 0.05) were significantly elevated at day 28 in theP. gingivalis-infected group compared to levels in the uninfected group. Correspondingly, RANKL-expressing T and B cells in rat gingival tissues were significantly increased at day 28 in theP. gingivalis-infected group compared to the levels in the uninfected group (P< 0.01). Injection of anti-RANKL antibody (P< 0.05) or OPG-Fc (P< 0.01), but not L6-Fc, into rat gingival papillae afterP. gingivalisinfection resulted in significantly reduced periodontal bone resorption. This study suggests thatP. gingivalisinfection-associated periodontal bone resorption is RANKL dependent and is accompanied by increased local infiltration of RANKL-expressing T and B cells.
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Britos, Maria Rosenda, Cynthya Solange Sin, Silvia Mercedes Ortega, and Olga Miriam Vasek. "Diseño y estandarización de la técnica de PCR para Porphyromonas gingivalis." Revista de la Facultad de Odontología 10, no. 1 (June 7, 2017): 25. http://dx.doi.org/10.30972/rfo.1012931.
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El objetivo del presente trabajo fue diseñar y estandarizar la técnica de PCR para detección en líquido gingival de Porphyromonas gingivalis, en pacientes con enfermedad periodontal. Material y métodos: Se utilizaron iniciadores específicos para el gen ARNr 16s de Porphyromonas gingivalis. La especificidad de los iniciadores se ensayó utilizando material genético extraído de la cepa de referencia Porphyromonas gingivalis ATCC 33277. Se ajustaron las condiciones de amplificación y concentraciones de la mezcla de reacción. Para validar la técnica se aplicó a diez muestras clínicas de líquido gingival de pacientes con enfermedad periodontal. Resultados: Se vizualizaron bandas nítidas a 197pb utilizando cebadores específicos en seis muestras clínicas, y se obtuvo sensibilidad hasta 15 ug/ml de ADN purificado de la cepa de referencia ATCC 33277.Conclusiones: Se validó y estandarizó una PCR sencilla para la detección de Porphyromonas gingivalis en líquido gingival
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Hasegawa, Yoshiaki, Gena D. Tribble, Henry V. Baker, Jeffrey J. Mans, Martin Handfield, and Richard J. Lamont. "Role of Porphyromonas gingivalis SerB in Gingival Epithelial Cell Cytoskeletal Remodeling and Cytokine Production." Infection and Immunity 76, no. 6 (April 7, 2008): 2420–27. http://dx.doi.org/10.1128/iai.00156-08.
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ABSTRACT The SerB protein of Porphyromonas gingivalis is a HAD family serine phosphatase that plays a critical role in entry and survival of the organism in gingival epithelial cells. SerB is secreted by P. gingivalis upon contact with epithelial cells. Here it is shown by microarray analysis that SerB impacts the transcriptional profile of gingival epithelial cells, with pathways involving the actin cytoskeleton and cytokine production among those significantly overpopulated with differentially regulated genes. Consistent with the transcriptional profile, a SerB mutant of P. gingivalis exhibited defective remodeling of actin in epithelial cells. Interaction between gingival epithelial cells and isolated SerB protein resulted in actin rearrangement and an increase in the F/G actin ratio. SerB protein was also required for P. gingivalis to antagonize interleukin-8 accumulation following stimulation of epithelial cells with Fusobacterium nucleatum. SerB is thus capable of modulating host cell signal transduction that impacts the actin cytoskeleton and cytokine production.
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Condorelli, Francesca, Guido Scalia, Giuditta Calì, Bruno Rossetti, Giuseppe Nicoletti, and Anna M. Lo Bue. "Isolation of Porphyromonas gingivalisand Detection of Immunoglobulin A Specific to Fimbrial Antigen in Gingival Crevicular Fluid." Journal of Clinical Microbiology 36, no. 8 (1998): 2322–25. http://dx.doi.org/10.1128/jcm.36.8.2322-2325.1998.
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The present study evaluated the prevalence of Porphyromonas gingivalis and the correlation between the bacterial culture method and the detection of immunoglobulin A (IgA) specific to theP. gingivalis fimbrial antigen in gingival crevicular fluid (GCF). P. gingivalis was isolated from 78.3% of subgingival plaque samples obtained from active sites and 34.7% of those from inactive sites of periodontal patients. P. gingivalis was isolated from only 4.7% of healthy subjects (control group). Immunoglobulins specific to the P. gingivalis fimbrial antigen were detected by enzyme-linked immunosorbent assay (ELISA). The overall agreement between the results of the P. gingivalis culture method and the results of specific IgA detection in periodontal patients was 71.7% for active sites and 58.7% for inactive sites. IgA specific to P. gingivalis was absent in GCF from all of the sites of healthy subjects. The results suggest that P. gingivalis is associated with the local production of specific IgA. The detection of IgA antibodies specific to P. gingivalis in GCF by ELISA may be used as a predictive parameter to reveal the early phase of the activation of recurrent periodontal infections.
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Eskan, Mehmet A., George Hajishengallis, and Denis F. Kinane. "Differential Activation of Human Gingival Epithelial Cells and Monocytes by Porphyromonas gingivalis Fimbriae." Infection and Immunity 75, no. 2 (November 21, 2006): 892–98. http://dx.doi.org/10.1128/iai.01604-06.
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ABSTRACT Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR). Porphyromonas gingivalis is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by P. gingivalis FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that P. gingivalis FimA does not readily activate epithelial innate immune responses but rather functions to promote P. gingivalis colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion, P. gingivalis FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by P. gingivalis when interacting with different host cell types or a host strategy to limit inflammation.
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Sao, Prachi, Yamini Chand, Atul Kumar, and Sachidanand Singh. "Potential Drug Target Identification in Porphyromonas gingivalis using In-silico Subtractive Metabolic Pathway Analysis." Bangladesh Journal of Medical Science 20, no. 4 (June 18, 2021): 887–96. http://dx.doi.org/10.3329/bjms.v20i4.54149.
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Introduction: Porphyromonas Gingivalis (P. gingivalis) a primary periodontal disease pathogen. This bacterium affects sub-gingival tissue and leads to loss of teeth and alveolar bone destruction in the acute stage. In recent years, P. gingivalis is often connected with other diseases such as rheumatoid arthritis, diabetes, Alzheimer’s, and heart disease, though the aetiology is still unclear.
Objective: The use of commonly available drugs to treat periodontitis results in various side effects, in particular multi-drug resistant strains. As the development of multidrugresistant strains frequently urges the identification of novel drug targets, the aim of this study is to identify specific targets in the narrow spectrum to combat oral pathogens.
Methodology: This study used a comparative and subtractive pathway analysis approach to identify potential drug targets specific to P. gingivalis.
Results: The in-silico comparison of the P. gingivalis and Homo sapiens (H. sapiens) metabolic pathways resulted in 13 unique pathogen pathways. A homology search of the 67 enzymes in the unique bacterial pathway using the BLASTp program against the Homo sapiens proteome resulted in fifteen possible targets that are non-homologous to the human proteome. Thirteen genes among 15 potent target encoders are key DEG genes indispensable for P. gingivalis’s survival. A comprehensive analysis of the literature identified three potential therapeutic drug targets.
Conclusions: The three most relevant drug targets are Arabinose-5-phosphate isomerase, UDP-2,3-diacylglucosamine hydrolase, and Undecaprenyl diphosphatase. Upon corroboration, these targets may give rise to narrow-spectrum antibiotics that can specificallytreat thedental infection.
Bangladesh Journal of Medical Science Vol.20(4) 2021 p.887-896
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Abiko, Y., M. Hayakawa, H. Aoki, and H. Takiguchi. "Gene Cloning and Expression of a Bacteroides Gingivalis-Specific Protein Antigen in Escherichia Coli." Advances in Dental Research 2, no. 2 (November 1988): 310–14. http://dx.doi.org/10.1177/08959374880020021801.
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Gene banks of chromosomal DNA from Bacteroides gingival is 381 were constructed utilizing the bacteriophage replacement vector λCharon4A. A clone encoding a protein antigen from B. gingivalis was identified by Western-blot screening, with use of antiserum induced to extracts of B. gingivalis cells. DNA fragments from the phage clone were subcloned into the plasmid vector pACYC184 to yield an immunoreactive clone. Cell extracts from the subclone reacted with antiserum against B. gingivalis, but did not react with antisera to B. asaccharolyticus, B. intermedius, or B. melaninogenicus. The antiserum against the purified clone products reacted with N-lauryl sarcosine extracts from B. gingivalis cells, but did not react with those of other Bacteroides cells. In addition, human serum from periodontitis patients reacted with the clone product by Western electrophoretic transfer and immunoblotting analysis. These data suggest that the gene coding for a B. gingivalis-specific protein antigen was successfully cloned and functionally expressed in Escherichia coli. This clone product may prove useful for further studies of B. gingival is as a periodontal pathogen.
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Andrian, E., D. Grenier, and M. Rouabhia. "Porphyromonas gingivalis-Epithelial Cell Interactions in Periodontitis." Journal of Dental Research 85, no. 5 (May 2006): 392–403. http://dx.doi.org/10.1177/154405910608500502.
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Emerging data on the consequences of the interactions between invasive oral bacteria and host cells have provided new insights into the pathogenesis of periodontal disease. Indeed, modulation of the mucosal epithelial barrier by pathogenic bacteria appears to be a critical step in the initiation and progression of periodontal disease. Periodontopathogens such as Porphyromonas gingivalis have developed different strategies to perturb the structural and functional integrity of the gingival epithelium. P. gingivalis adheres to, invades, and replicates within human epithelial cells. Adhesion of P. gingivalis to host cells is multimodal and involves the interaction of bacterial cell-surface adhesins with receptors expressed on the surfaces of epithelial cells. Internalization of P. gingivalis within host cells is rapid and requires both bacterial contact-dependent components and host-induced signaling pathways. P. gingivalis also subverts host responses to bacterial challenges by inactivating immune cells and molecules and by activating host processes leading to tissue destruction. The adaptive ability of these pathogens that allows them to survive within host cells and degrade periodontal tissue constituents may contribute to the initiation and progression of periodontitis. In this paper, we review current knowledge on the molecular cross-talk between P. gingivalis and gingival epithelial cells in the development of periodontitis.
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Chaudhuri, Swarnava, Siddharth Pratap, Victor Paromov, Zhijun Li, Chinmay K. Mantri, and Hua Xie. "Identification of a Diguanylate Cyclase and Its Role in Porphyromonas gingivalis Virulence." Infection and Immunity 82, no. 7 (April 14, 2014): 2728–35. http://dx.doi.org/10.1128/iai.00084-14.
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ABSTRACTPorphyromonas gingivalisis a Gram-negative obligate anaerobic bacterium and is considered a keystone pathogen in the initiation of periodontitis, one of the most widespread infectious diseases. Bacterial bis-(3′-5′) cyclic GMP (cyclic di-GMP [c-di-GMP]) serves as a second messenger and is involved in modulating virulence factors in numerous bacteria. However, the role of this second messenger has not been investigated inP. gingivalis, mainly due to a lack of an annotation regarding diguanylate cyclases (DGCs) in this bacterium. Using bioinformatics tools, we found a protein, PGN_1932, containing a GGDEF domain. A deletion mutation in thepgn_1932gene had a significant effect on the intracellular c-di-GMP level inP. gingivalis. Genetic analysis showed that expression of thefimAandrgpAgenes, encoding the major protein subunit of fimbriae and an arginine-specific proteinase, respectively, was downregulated in thepgn_1932mutant. Correspondingly, FimA protein production and the fimbrial display on the mutant were significantly reduced. Mutations in thepgn_1932gene also had a significant impact on the adhesive and invasive capabilities ofP. gingivalis, which are required for its pathogenicity. These findings provide evidence that the PGN_1932 protein is both responsible for synthesizing c-di-GMP and involved in biofilm formation and host cell invasion byP. gingivalisby controlling the expression and biosynthesis of FimA.
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Jauregui, Catherine E., Qian Wang, Christopher J. Wright, Hiroki Takeuchi, Silvia M. Uriarte, and Richard J. Lamont. "Suppression of T-Cell Chemokines by Porphyromonas gingivalis." Infection and Immunity 81, no. 7 (April 15, 2013): 2288–95. http://dx.doi.org/10.1128/iai.00264-13.
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ABSTRACTPorphyromonas gingivalisis a major pathogen in periodontal disease and is associated with immune dysbiosis. In this study, we found thatP. gingivalisdid not induce the expression of the T-cell chemokine IP-10 (CXCL10) from neutrophils, peripheral blood mononuclear cells (PBMCs), or gingival epithelial cells. Furthermore,P. gingivalissuppressed gamma interferon (IFN-γ)-stimulated release of IP-10, ITAC (CXCL11), and Mig (CXCL9) from epithelial cells and inhibited IP-10 secretion in a mixed infection with the otherwise stimulatoryFusobacterium nucleatum. Inhibition of chemokine expression occurred at the level of gene transcription and was associated with downregulation of interferon regulatory factor 1 (IRF-1) and decreased levels of Stat1. Ectopic expression of IRF-1 in epithelial cells relievedP. gingivalis-induced inhibition of IP-10 release. Direct contact betweenP. gingivalisand epithelial cells was not required for IP-10 inhibition. These results highlight the immune-disruptive potential ofP. gingivalis. Suppression of IP-10 and other Th1-biasing chemokines byP. gingivalismay perturb the balance of protective and destructive immunity in the periodontal tissues and facilitate the pathogenicity of oral microbial communities.
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Naito, Y., and R. J. Gibbons. "Attachment of Bacteroides gingivalis to Collagenous Substrata." Journal of Dental Research 67, no. 8 (August 1988): 1075–80. http://dx.doi.org/10.1177/00220345880670080301.
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The ability of Bacteroides gingivalis 381 to attach to hydroxyapatite (HA) beads, treated with either human type I or type IV collagen, or to particles of bovine bone collagen was studied. All preparations were blocked with human albumin prior to being incubated with 3H-thymidine-labeled B. gingivalis 381 cells. The presence of collagen on HA surfaces (C-HA) significantly promoted attachment of the organism. HA treated with Type IV collagen bound B. gingivalis cells more effectively than did HA treated with type I collagen. Attachment of two additional strains of B. gingivalis to HA was also promoted by collagen. Binding to type I or type IV C-HA occurred rapidly, and equilibrium was attained within 45 min. B. gingivalis 381 cells also bound to particles of bovine bone collagen, and this appeared to be biphasic. Heating the bacteria abolished their ability to bind to C-HA. Attachment of B. gingivalis 381 cells to HA treated with type I collagen was strongly inhibited by the presence of soluble type I or type IV collagen, or gelatin, but not by the presence of human albumin, salivary proline-rich protein 1, or saliva. Human serum, fibronectin, fibrinogen, certain protease inhibitors, and some peptides were also inhibitory. 3H-fibronectin bound to bovine bone collagen particles and blocked the attachment of 14C-B. gingivalis cells. Mild trypsin treatment of the fibronectin-collagen complex restored its ability to promote 14C-B. gingivalis attachment concomitant with the loss of 3H-fibronectin. We suggest that elevated levels of proteases in the gingival sulcus, such as are associated with poor oral hygiene and gingivitis, might remove fibronectin and expose collagen molecules in the basement membrane, thereby promoting the attachment of B. gingivalis cells and facilitating their invasion into gingival tissues.
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Bainbridge, Brian, Raj K. Verma, Christie Eastman, Bilal Yehia, Mercedes Rivera, Catherine Moffatt, Indraneel Bhattacharyya, Richard J. Lamont, and Lakshmyya Kesavalu. "Role of Porphyromonas gingivalis Phosphoserine Phosphatase Enzyme SerB in Inflammation, Immune Response, and Induction of Alveolar Bone Resorption in Rats." Infection and Immunity 78, no. 11 (August 30, 2010): 4560–69. http://dx.doi.org/10.1128/iai.00703-10.
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ABSTRACT Porphyromonas gingivalis secretes a serine phosphatase enzyme, SerB, upon contact with gingival epithelial cells in vitro. The SerB protein plays a critical role in internalization and survival of the organism in epithelial cells. SerB is also responsible for the inhibition of interleukin-8 (IL-8) secretion from gingival epithelial cells infected with P. gingivalis. This study examined the ability of a P. gingivalis SerB mutant to colonize the oral cavity and induce gingival inflammation, immune responses, and alveolar bone resorption in a rat model of periodontal disease. Both P. gingivalis ATCC 33277 and an isogenic ΔSerB mutant colonized the oral cavities of rats during the 12-week experimental period. Both of the strains induced significant (P < 0.05) systemic levels of immunoglobulin G (IgG) and isotypes IgG1, IgG2a, and IgG2b, indicating the involvement of both T helper type 1 (Th1) and Th2 responses to infection. Both strains induced significantly (P < 0.05) higher levels of alveolar bone resorption in infected rats than in sham-infected control rats. However, horizontal and interproximal alveolar bone resorption induced by the SerB mutant was significantly (P < 0.05) lower than that induced by the parental strain. Rats infected with the ΔSerB mutant exhibited significantly higher levels of apical migration of the junctional epithelium (P < 0.01) and polymorphonuclear neutrophil (PMN) recruitment (P < 0.001) into the gingival tissues than rats infected with the wild type. In conclusion, in a rat model of periodontal disease, the SerB phosphatase of P. gingivalis is required for maximal alveolar bone resorption, and in the absence of SerB, more PMNs are recruited into the gingival tissues.
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Watanabe, Kiyoko, Özlem Yilmaz, Simin F. Nakhjiri, Carol M. Belton, and Richard J. Lamont. "Association of Mitogen-Activated Protein Kinase Pathways with Gingival Epithelial Cell Responses to Porphyromonas gingivalis Infection." Infection and Immunity 69, no. 11 (November 1, 2001): 6731–37. http://dx.doi.org/10.1128/iai.69.11.6731-6737.2001.
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ABSTRACT Mitogen-activated protein (MAP) kinase pathways are key factors in host signaling events and can also play important roles in the internalization of pathogenic bacteria by host cells.Porphyromonas gingivalis, a periodontal pathogen, can efficiently invade human gingival epithelial cells (GECs). In this study, we examined the activation of MAP kinase pathways in GECs infected with P. gingivalis. c-Jun N-terminal kinase (JNK) was activated after 5 min of infection with P. gingivalis, whereas noninvasiveStreptococcus gordonii did not have a significant effect on JNK activation. In contrast, extracellular signal-regulated kinase (ERK) 1/2 was downregulated in a dose-dependent manner by P. gingivalis, but not by S. gordonii, after a 15-min exposure. Nonmetabolically active P. gingivaliscells were unable to modulate MAP kinase activity. U0126, a specific inhibitor of MEK1/2 (ERK1/2 kinase), and toxin B, a specific inhibitor of Rho family GTPases, had no effect on P. gingivalis invasion. Genistein, a tyrosine protein kinase inhibitor, blocked uptake of P. gingivalis. The transcriptional regulator NF-κB was not activated by P. gingivalis. These results suggest that P. gingivalis can selectively target components of the MAP kinase pathways. ERK1/2, while not involved in P. gingivalisinvasion of GECs, may be downregulated by internalized P. gingivalis. Activation of JNK is associated with the invasive process of P. gingivalis.
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Park, Yoonsuk, and Richard J. Lamont. "Contact-Dependent Protein Secretion inPorphyromonas gingivalis." Infection and Immunity 66, no. 10 (October 1, 1998): 4777–82. http://dx.doi.org/10.1128/iai.66.10.4777-4782.1998.
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ABSTRACT Porphyromonas gingivalis can induce its uptake by host epithelial cells; however, the nature and role of the P. gingivalis molecules involved in this invasion process have yet to be determined. In this study, modulation of secreted P. gingivalis proteins following association with gingival epithelial cells was investigated. Western immunoblot analysis showed that contact with epithelial cells or epithelial cell growth media induces P. gingivalis 33277 to secrete several proteins with molecular masses between 35 and 95 kDa. Secretion of the Arg-gingipain and Lys-gingipain proteases was repressed under these conditions. The contact-induced secreted protein profile was altered in Arg-gingipain-deficient and Lys-gingipain-deficient mutants, indicating a possible role for these proteases in the secretion pathway. TheP. gingivalis contact-dependent protein secretion pathway differs to some extent from type III protein secretion pathways in enteric pathogens, as a gene homologous to the invA family genes was not detected in P. gingivalis. The secreted proteins of P. gingivalis may play a role in the interactions of the organism with host cells.
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Mulhall, Hannah, Jeanne M. DiChiara, Matthew Deragon, Radha Iyer, Olivier Huck, and Salomon Amar. "Akkermansia muciniphila and Its Pili-Like Protein Amuc_1100 Modulate Macrophage Polarization in Experimental Periodontitis." Infection and Immunity 89, no. 1 (October 5, 2020): e00500-20. http://dx.doi.org/10.1128/iai.00500-20.
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ABSTRACTPeriodontitis is a chronic inflammatory disease triggered by dysbiosis of the oral microbiome. Porphyromonas gingivalis is strongly implicated in periodontal inflammation, gingival tissue destruction, and alveolar bone loss through sustained exacerbation of the host response. Recently, the use of other bacterial species, such as Akkermansia muciniphila, has been suggested to counteract inflammation elicited by P. gingivalis. In this study, the effects of A. muciniphila and its pili-like protein Amuc_1100 on macrophage polarization during P. gingivalis infection were evaluated in a murine model of experimental periodontitis. Mice were gavaged with P. gingivalis alone or in combination with A. muciniphila or Amuc_1100 for 6 weeks. Morphometric analysis demonstrated that the addition of A. muciniphila or Amuc_1100 significantly reduced P. gingivalis-induced alveolar bone loss. This decreased bone loss was associated with a proresolutive phenotype (M2) of macrophages isolated from submandibular lymph nodes as observed by flow cytometry. Furthermore, the expression of interleukin 10 (IL-10) at the RNA and protein levels was significantly increased in the gingival tissues of the mice and in macrophages exposed to A. muciniphila or Amuc_1100, confirming their anti-inflammatory properties. This study demonstrates the putative therapeutic interest of the administration of A. muciniphila or Amuc_1100 in the management of periodontitis through their anti-inflammatory properties.
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Bugueno, Isaac M., Nadia Benkirane-Jessel, and Olivier Huck. "Implication of Toll/IL-1 receptor domain containing adapters in Porphyromonas gingivalis-induced inflammation." Innate Immunity 27, no. 4 (May 2021): 324–42. http://dx.doi.org/10.1177/17534259211013087.
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Periodontitis is induced by periodontal dysbiosis characterized by the predominance of anaerobic species. TLRs constitute the classical pathway for cell activation by infection. Interestingly, the Toll/IL-1 receptor homology domain adapters initiate signaling events, leading to the activation of the expression of the genes involved in the host immune response. The aim of this study was to evaluate the effects of Porphyromonas gingivalis on the expression and protein-protein interactions among five TIR adapters (MAL, MyD88, TRIF, TRAM and SARM) in gingival epithelial cells and endothelial cells. It was observed that P. gingivalis is able to modulate the signaling cascades activated through its recognition by TLR4/2 in gingival epithelial cells and endothelial cells. Indeed, MAL-MyD88 protein-protein interactions associated with TLR4 was the main pathway activated by P. gingivalis infection. When transient siRNA inhibition was performed, cell viability, inflammation, and cell death induced by infection decreased and such deleterious effects were almost absent when MAL or TRAM were targeted. This study emphasizes the role of such TIR adapter proteins in P. gingivalis elicited inflammation and the precise evaluation of TIR adapter protein interactions may pave the way for future therapeutics in both periodontitis and systemic disease with a P. gingivalis involvement, such as atherothrombosis.
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O'Brien-Simpson, Neil M., Rishi D. Pathirana, Glenn D. Walker, and Eric C. Reynolds. "Porphyromonas gingivalis RgpA-Kgp Proteinase-Adhesin Complexes Penetrate Gingival Tissue and Induce Proinflammatory Cytokines or Apoptosis in a Concentration-Dependent Manner." Infection and Immunity 77, no. 3 (December 29, 2008): 1246–61. http://dx.doi.org/10.1128/iai.01038-08.
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ABSTRACT The RgpA-Kgp proteinase-adhesin complexes of Porphyromonas gingivalis were observed, using immunostaining, in human gingival tissue associated with periodontitis but not in healthy tissue. The staining pattern suggested a concentration gradient from the subgingival plaque into the subjacent gingival connective tissue. Intense immunostaining was observed in areas displaying gross disturbance of tissue architecture. P. gingivalis cells and the RgpA-Kgp complexes at low concentrations were shown to stimulate secretory intercellular adhesion molecule 1, interleukin-8 (IL-8), IL-6, and macrophage chemoattractant protein secretion from cultured human epithelial (KB) and fibroblast (MRC-5) cells. However, at high concentrations a reduction in the level of these mediators was observed. In contrast, macrophage inflammatory protein 1α and IL-1α were stimulated only at high P. gingivalis cell concentrations. P. gingivalis cells and the RgpA-Kgp complexes were shown to induce apoptosis in KB and MRC-5 cells in a time- and dose-dependent manner. These data suggest that the RgpA-Kgp complexes penetrate the gingival connective tissue; at low concentrations distal from the plaque the complexes stimulate the secretion of proinflammatory mediators, while at high concentrations proximal to the plaque they induce apoptosis and attenuate the secretion of proinflammatory mediators.
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Tsai, Tzung-Hsun, Chi-I. Chang, Ya-Ling Hung, Wen-Cheng Huang, Hsiang Chang, Yueh-Hsiung Kuo, Jong-Ho Chyuan, Lu-Te Chuang, and Po-Jung Tsai. "Anti-Inflammatory Effect of Charantadiol A, Isolated from Wild Bitter Melon Leaf, on Heat-Inactivated Porphyromonas gingivalis-Stimulated THP-1 Monocytes and a Periodontitis Mouse Model." Molecules 26, no. 18 (September 17, 2021): 5651. http://dx.doi.org/10.3390/molecules26185651.
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Porphyromonas gingivalis has been identified as one of the major periodontal pathogens. Activity-directed fractionation and purification processes were employed to identify bioactive compounds from bitter melon leaf. Ethanolic extract of bitter melon leaf was separated into five subfractions by open column chromatography. Subfraction-5-3 significantly inhibited P. gingivalis-induced interleukin (IL)-8 and IL-6 productions in human monocytic THP-1 cells and then was subjected to separation and purification by using different chromatographic methods. Consequently, 5β,19-epoxycucurbita-6,23(E),25(26)-triene-3β,19(R)-diol (charantadiol A) was identified and isolated from the subfraction-5-3. Charantadiol A effectively reduced P. gingivalis-induced IL-6 and IL-8 productions and triggered receptors expressed on myeloid cells (TREM)-1 mRNA level of THP-1 cells. In a separate study, charantadiol A significantly suppressed P. gingivalis-stimulated IL-6 and tumor necrosis factor-α mRNA levels in gingival tissues of mice, confirming the inhibitory effect against P. gingivalis-induced periodontal inflammation. Thus, charantadiol A is a potential anti-inflammatory agent for modulating P. gingivalis-induced inflammation.
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Andrian, Elisoa, Daniel Grenier, and Mahmoud Rouabhia. "In Vitro Models of Tissue Penetration and Destruction by Porphyromonas gingivalis." Infection and Immunity 72, no. 8 (August 2004): 4689–98. http://dx.doi.org/10.1128/iai.72.8.4689-4698.2004.
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ABSTRACT Porphyromonas gingivalis is a gram-negative anaerobic bacterium that is considered the key etiologic agent of chronic periodontitis. Arg- and Lys-gingipain cysteine proteinases produced by P. gingivalis are key virulence factors and are believed to be essential for significant tissue component degradation, leading to host tissue invasion by periodontopathogens. Two in vitro models were used to determine the extent to which P. gingivalis can reach connective tissue. The tissue penetration potential of P. gingivalis was first investigated by using an engineered human oral mucosa model composed of normal human epithelial cells and fibroblasts. Internalized bacteria were assessed by transmission electron microscopy. Bacteria were observed within multilayered gingival epithelial cells and in the space between the stratified epithelium and the lamina propria. A gingipain-null mutant strain of P. gingivalis was found to be less potent in penetrating tissue than the wild-type strain. Proinflammatory responses to P. gingivalis infection were evaluated. P. gingivalis increased the secretion of interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor alpha. In the second part of the study, the contribution of P. gingivalis gingipains to tissue penetration was investigated by using a reconstituted basement membrane model (Matrigel). The penetration of 14C-labeled P. gingivalis cells through Matrigel was significantly reduced when leupeptin, a specific inhibitor of Arg-gingipain activity, was added or when a gingipain-null mutant was used. The results obtained with these two relevant models support the capacities of P. gingivalis to infiltrate periodontal tissue and to modulate the proinflammatory response and suggest a critical role of gingipains in tissue destruction.
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Nisapakultorn, K., K. F. Ross, and M. C. Herzberg. "Calprotectin Expression In Vitro by Oral Epithelial Cells Confers Resistance to Infection by Porphyromonas gingivalis." Infection and Immunity 69, no. 7 (July 1, 2001): 4242–47. http://dx.doi.org/10.1128/iai.69.7.4242-4247.2001.
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ABSTRACT Calprotectin, an S100 calcium-binding protein with broad-spectrum antimicrobial activity in vitro, is expressed in neutrophils, monocytes, and gingival keratinocytes. In periodontitis, calprotectin appears upregulated and is detected at higher levels in gingival crevicular fluid and tissue specimens. How calprotectin contributes to the pathogenesis of periodontal diseases is unknown. To isolate the effects of calprotectin, a calprotectin-negative oral epithelial cell line was transfected with calprotectin genes to enable expression.Porphyromonas gingivalis was permitted to bind and invade transfected cells expressing calprotectin and sham transfectants. Rates of invasion into both cell lines were compared using the antibiotic protection assay. Transfected cells expressing calprotectin showed 40 to 50% fewer internalized P. gingivalis than sham transfectants. Similarly, binding to calprotectin expressing cells was reduced approximately twofold at all time points (15, 30, 45, and 60 min) as estimated by immunofluorescence analysis. Independent of invasion, however, prolonged exposure to P. gingivalisinduced epithelial cell rounding and detachment from the substratum. These morphological changes were delayed, however, in cells expressing calprotectin. Using P. gingivalis protease-deficient mutants, we found that Arg-gingipain and Lys-gingipain contributed to epithelial cell rounding and detachment. In conclusion, expression of calprotectin appears to protect epithelial cells in culture against binding and invasion by P. gingivalis. In addition, cells expressing calprotectin are more resistant to detachment mediated by Arg-gingipain and Lys-gingipain. In periodontal disease, calprotectin may augment both the barrier protection and innate immune functions of the gingival epithelium to promote resistance to P. gingivalis infection.
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Wang, Huizhi, Huaxin Zhou, Xiaoxian Duan, Ravi Jotwani, Himabindu Vuddaraju, Shuang Liang, David A. Scott, and Richard J. Lamont. "Porphyromonas gingivalis-Induced Reactive Oxygen Species Activate JAK2 and Regulate Production of Inflammatory Cytokines through c-Jun." Infection and Immunity 82, no. 10 (July 21, 2014): 4118–26. http://dx.doi.org/10.1128/iai.02000-14.
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ABSTRACTPathogen-induced reactive oxygen species (ROS) play a crucial role in host innate immune responses through regulating the quality and quantity of inflammatory mediators. However, the underlying molecular mechanisms of this effect have yet to be clarified. In this study, we examined the mechanism of action of ROS stimulated byPorphyromonas gingivalisin gingival epithelial cells.P. gingivalisinduced the rapid production of ROS, which lead to the phosphorylation of JAK2 and increased levels of secreted proinflammatory cytokines interleukin-6 (IL-6) and IL-1β. Neutralization of ROS byN-acetyl-l-cysteine (NAC) abrogated the phosphorylation of JAK2 and suppressed the production of IL-6 and IL-1β. ROS-mediated phosphorylation of JAK2 induced the phosphoactivation of c-Jun amino-terminal protein kinase (JNK) and the downstream transcriptional regulator c-Jun. Inhibition of JAK2, either pharmacologically or by small interfering RNA (siRNA), reduced both the phosphorylation of these molecules and the production of proinflammatory cytokines in response toP. gingivalis. Furthermore, pharmacological inhibition or siRNA-mediated gene silencing of JNK or c-Jun mimicked the effect of JAK2 inhibition to suppressP. gingivalis-induced IL-6 and IL-1β levels. The results show that ROS-mediated activation of JAK2 is required forP. gingivalis-induced inflammatory cytokine production and that the JNK/c-Jun signaling axis is involved in the ROS-dependent regulation of IL-1β and IL-6 production.
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Xie, Hua, and Cunge Zheng. "OxyR Activation in Porphyromonas gingivalis in Response to a Hemin-Limited Environment." Infection and Immunity 80, no. 10 (July 23, 2012): 3471–80. http://dx.doi.org/10.1128/iai.00680-12.
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ABSTRACTPorphyromonas gingivalisis a Gram-negative obligately anaerobic bacterium associated with several forms of periodontal disease, most closely with chronic periodontitis. Previous studies demonstrated that OxyR plays an important role in the aerotolerance ofP. gingivalisby upregulating the expression of oxidative-stress genes. Increases in oxygen tension and in H2O2both induce activation of OxyR. It is also known thatP. gingivalisrequires hemin as an iron source for its growth. In this study, we found that a hemin-limited growth environment significantly enhanced OxyR activity inP. gingivalis. As a result, expression ofsod,dps, andahpCwas also upregulated. Using a chromatin immunoprecipitation quantitative PCR (qPCR) analysis, DNA binding of activated OxyR to the promoter of thesodgene was enhanced inP. gingivalisgrown under hemin-limited conditions compared to excess-hemin conditions. Cellular tolerance of H2O2was also enhanced when hemin was limited in the growth medium ofP. gingivalis. Our work supports a model in which hemin serves as a signal for the regulation of OxyR activity and indicates thatP. gingivaliscoordinately regulates expression of oxidative-stress-related genes by this hemin concentration-dependent pathway.
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Bhatti, M., A. MacRobert, B. Henderson, P. Shepherd, J. Cridland, and M. Wilson. "Antibody-Targeted Lethal Photosensitization ofPorphyromonas gingivalis." Antimicrobial Agents and Chemotherapy 44, no. 10 (October 1, 2000): 2615–18. http://dx.doi.org/10.1128/aac.44.10.2615-2618.2000.
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ABSTRACT We have previously demonstrated that Porphyromonas gingivalis is susceptible to killing by toluidine blue O (TBO) when irradiated with light from a helium-neon (HeNe) laser. The aim of this study was to determine whether a TBO-antibody conjugate (Ab-TBO) could be used to specifically target P. gingivalis to lethal photosensitization in the presence ofStreptococcus sanguis or human gingival fibroblasts (HGFs). When a mixture of P. gingivalis and S. sanguiswas exposed to 4 μg of TBO/ml and irradiated with HeNe laser light, there were 1.5- and 4.0-log10-unit reductions in the viable counts, respectively. In contrast, when TBO was conjugated with a murine monoclonal antibody against P. gingivalislipopolysaccharide, the reductions in viable counts of P. gingivalis and S. sanguis amounted to 5.0 and 0.1 log10 units, respectively. Lethal photosensitization ofP. gingivalis in the presence of HGFs using unconjugated TBO resulted in a 0.7-log10-unit reduction in P. gingivalis viable counts and a 99% reduction in the incorporation of tritiated thymidine ([3H]Tdr) by the HGFs. In contrast, when the Ab-TBO conjugate was used, there was a 100% reduction in P. gingivalis viable counts but no significant reduction in the incorporation of [3H]Tdr by HGFs. These results demonstrate that specific targeting of P. gingivalis can be achieved using TBO conjugated to a monoclonal antibody raised against a cell surface component of this organism.
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Yilmaz, Özlem, Patrick A. Young, Richard J. Lamont, and George E. Kenny. "Gingival epithelial cell signalling and cytoskeletal responses to Porphyromonas gingivalis invasion." Microbiology 149, no. 9 (September 1, 2003): 2417–26. http://dx.doi.org/10.1099/mic.0.26483-0.
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Porphyromonas gingivalis, an oral pathogen, can internalize within primary gingival epithelial cells (GECs) through an invasion mechanism mediated by interactions between P. gingivalis fimbriae and integrins on the surface of the GECs. Fimbriae–integrin-based signalling events were studied by fluorescence microscopy, and the subcellular localization of integrin-associated signalling molecules paxillin and focal adhesion kinase (FAK), and the architecture of the actin and microtubule cytoskeleton were examined. GECs infected with P. gingivalis for 30 min demonstrated significant redistribution of paxillin and FAK from the cytosol to cell peripheries and assembly into focal adhesion complexes. In contrast, a fimbriae-deficient mutant of P. gingivalis did not contribute substantially to activation of paxillin or FAK. After 24 h, the majority of paxillin and FAK had returned to the cytoplasm with significant co-localization with P. gingivalis in the perinuclear region. Wild-type P. gingivalis induced nucleation of actin filaments forming microspike-like protrusions and long stable microfilaments distributed throughout the cells. Fimbriae mutants promoted a rich cortical actin meshwork accompanied by membrane ruffling dispersed along the cell membrane. Remarkable disassembly and nucleation of the actin and microtubule filamentous network was observed following 24 h infection with either wild-type or fimbriae-deficient mutants of P. gingivalis. The results show that fimbriated P. gingivalis cells induce formation of integrin-associated focal adhesions with subsequent remodelling of the actin and tubulin cytoskeleton.
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Tamai, Riyoko, Michiyo Kobayashi-Sakamoto, and Yusuke Kiyoura. "Extracellular galectin-1 enhances adhesion to and invasion of oral epithelial cells by Porphyromonas gingivalis." Canadian Journal of Microbiology 64, no. 7 (July 2018): 465–71. http://dx.doi.org/10.1139/cjm-2017-0461.
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Galectin-1 and galectin-3 are C-type lectin receptors that bind to lipopolysaccharide in the cell wall of gram-negative bacteria. In this study, we investigated the effects of galectin-1 and galectin-3 on adhesion to and invasion of the human gingival epithelial cell line Ca9-22 by Porphyromonas gingivalis, a periodontal pathogenic gram-negative bacterium. Recombinant galectin-1, but not galectin-3, enhanced P. gingivalis adhesion and invasion, although both galectins bound similarly to P. gingivalis. Flow cytometry also revealed that Ca9-22 cells express low levels of galectin-1 and moderate levels of galectin-3. Ca9-22 cells in which galectin-3 was knocked-down did not exhibit enhanced P. gingivalis adhesion and invasion. Similarly, specific antibodies to galectin-1 and galectin-3 did not inhibit P. gingivalis adhesion and invasion. These results suggest that soluble galectin-1, but not galectin-3, may exacerbate periodontal disease by enhancing the adhesion to and invasion of host cells by periodontal pathogenic bacteria.
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Shah, H. N., S. E. Gharbia, D. Kowlessur, E. Wilkie, and K. Brocklehurst. "Gingivain; A Cysteine Proteinase Isolated fromPorphyromonas gingivalis." Microbial Ecology in Health and Disease 4, no. 5 (January 1991): 319–28. http://dx.doi.org/10.3109/08910609109140282.
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Memedovski, Zylfi, Evan Czerwonka, Jin Han, Joshua Mayer, Margaret Luce, Lucas C. Klemm, Mary L. Hall, and Alejandro M. S. Mayer. "Classical and Alternative Activation of Rat Microglia Treated with Ultrapure Porphyromonas gingivalis Lipopolysaccharide In Vitro." Toxins 12, no. 5 (May 19, 2020): 333. http://dx.doi.org/10.3390/toxins12050333.
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The possible relationship between periodontal disease resulting from the infection of gingival tissue by the Gram-negative bacterium Porphyromonas gingivalis (P. gingivalis) and the development of neuroinflammation remains under investigation. Recently, P. gingivalis lipopolysaccharide (LPS) was reported in the human brain, thus suggesting it might activate brain microglia, a cell type participating in neuroinflammation. We tested the hypothesis of whether in vitro exposure to ultrapure P. gingivalis LPS may result in classical and alternative activation phenotypes of rat microglia, with the concomitant release of cytokines and chemokines, as well as superoxide anion (O2−), thromboxane B2 (TXB2), and matrix metalloprotease-9 (MMP-9). After an 18-h exposure of microglia to P. gingivalis LPS, the concentration-dependent responses were the following: 0.1–100 ng/mL P. gingivalis LPS increased O2− generation, with reduced inflammatory mediator generation; 1000–10,000 ng/mL P. gingivalis LPS generated MMP-9, macrophage inflammatory protein 1α (MIP-1α/CCL3), macrophage inflammatory protein-2 (MIP-2/CXCL2) release and significant O2− generation; 100,000 ng/mL P. gingivalis LPS sustained O2− production, maintained MMP-9, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) release, and triggered elevated levels of MIP-1α/CCL3, MIP-2/CXCL2, and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL-1), with a very low release of lactic dehydrogenase (LDH). Although P. gingivalis LPS was less potent than Escherichia coli (E. coli) LPS in stimulating TXB2, MMP-9, IL-6 and interleukin 10 (IL-10) generation, we observed that it appeared more efficacious in enhancing the release of O2−, TNF-α, MIP-1α/CCL3, MIP-2/CXCL2 and CINC-1/CXCL-1. Our results provide support to our research hypothesis because an 18-h in vitro stimulation with ultrapure P. gingivalis LPS resulted in the classical and alternative activation of rat brain microglia and the concomitant release of cytokines and chemokines.
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Wang, Yu-Hsiung, Jin Jiang, Qiang Zhu, Amer Z. AlAnezi, Robert B. Clark, Xi Jiang, David W. Rowe, and Frank C. Nichols. "Porphyromonas gingivalis Lipids Inhibit Osteoblastic Differentiation and Function." Infection and Immunity 78, no. 9 (June 28, 2010): 3726–35. http://dx.doi.org/10.1128/iai.00225-10.
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ABSTRACT Porphyromonas gingivalis produces unusual sphingolipids that are known to promote inflammatory reactions in gingival fibroblasts and Toll-like receptor 2 (TLR2)-dependent secretion of interleukin-6 from dendritic cells. The aim of the present study was to examine whether P. gingivalis lipids inhibit osteoblastic function. Total lipids from P. gingivalis and two fractions, phosphoglycerol dihydroceramides and phosphoethanolamine dihydroceramides, were prepared free of lipid A. Primary calvarial osteoblast cultures derived from 5- to 7-day-old CD-1 mice were used to examine the effects of P. gingivalis lipids on mineralized nodule formation, cell viability, apoptosis, cell proliferation, and gene expression. P. gingivalis lipids inhibited osteoblast differentiation and fluorescence expression of pOBCol2.3GFP in a concentration-dependent manner. However, P. gingivalis lipids did not significantly alter osteoblast proliferation, viability, or apoptosis. When administered during specific intervals of osteoblast growth, P. gingivalis total lipids demonstrated inhibitory effects on osteoblast differentiation only after the proliferation stage of culture. Reverse transcription-PCR confirmed the downregulation of osteoblast marker genes, including Runx2, ALP, OC, BSP, OPG, and DMP-1, with concurrent upregulation of RANKL, tumor necrosis factor alpha, and MMP-3 genes. P. gingivalis total lipids and lipid fractions inhibited calvarial osteoblast gene expression and function in vivo, as determined by the loss of expression of another osteoblast differentiation reporter, pOBCol3.6GFPcyan, and reduced uptake of Alizarin complexone stain. Finally, lipid inhibition of mineral nodule formation in vitro was dependent on TLR2 expression. Our results indicate that inhibition of osteoblast function and gene expression by P. gingivalis lipids represents a novel mechanism for altering alveolar bone homeostasis at periodontal disease sites.
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Lamont, R. J., A. Chan, C. M. Belton, K. T. Izutsu, D. Vasel, and A. Weinberg. "Porphyromonas gingivalis invasion of gingival epithelial cells." Infection and immunity 63, no. 10 (1995): 3878–85. http://dx.doi.org/10.1128/iai.63.10.3878-3885.1995.
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Kesavalu, L., B. Vasudevan, B. Raghu, E. Browning, D. Dawson, J. M. Novak, M. C. Correll, et al. "Omega-3 Fatty Acid Effect on Alveolar Bone Loss in Rats." Journal of Dental Research 85, no. 7 (July 2006): 648–52. http://dx.doi.org/10.1177/154405910608500713.
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Gingival inflammation and alveolar bone resorption are hallmarks of adult periodontitis, elicited in response to oral micro-organisms such as Porphyromonas gingivalis. We hypothesized that omega (ω)-3 fatty acids (FA) dietary supplementation would modulate inflammatory reactions leading to periodontal disease in infected rats. Rats were fed fish oil (ω-3 FA) or corn oil (n-6 FA) diets for 22 weeks and were infected with P. gingivalis. Rats on the ω-3 FA diet exhibited elevated serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), documenting diet-induced changes. PCR analyses demonstrated that rats were orally colonized by P. gingivalis; increased IgG antibody levels substantiated this infection. P. gingivalis-infected rats treated with ω-3 FA had significantly less alveolar bone resorption. These results demonstrated the effectiveness of an ω-3 FA-supplemented diet in modulating alveolar bone resorption following P. gingivalis infection, and supported that ω-3 FA may be a useful adjunct in the treatment of periodontal disease. Abbreviations: PUFA, polyunsaturated fatty acid; EPA, eicosapentanoic acid; DHA, docosahexanoic acid; and PCR, polymerase chain-reaction.
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Park, Yoonsuk, Özlem Yilmaz, Il-Young Jung, and Richard J. Lamont. "Identification of Porphyromonas gingivalis Genes Specifically Expressed in Human Gingival Epithelial Cells by Using Differential Display Reverse Transcription-PCR." Infection and Immunity 72, no. 7 (July 2004): 3752–58. http://dx.doi.org/10.1128/iai.72.7.3752-3758.2004.
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ABSTRACT Porphyromonas gingivalis, one of the causative agents of adult periodontitis, can invade and survive within host epithelial cells. The molecular mechanisms by which P. gingivalis induces uptake and adapts to an intracellular environment are not fully understood. In this study, we have investigated the genetic responses of P. gingivalis internalized within human gingival epithelial cells (GECs) in order to identify factors involved in invasion and survival. We compared the differential display of arbitrarily PCR-amplified gene transcripts in P. gingivalis recovered from GECs with the display of transcripts in P. gingivalis control cultures. Over 20 potential differentially expressed transcripts were identified. Among these, pepO, encoding an endopeptidase, and genes encoding an ATP-binding cassette (ABC) transporter and a cation-transporting ATPase were upregulated in GECs. To investigate the functionality of these gene products, mutants were generated by insertional inactivation. Compared to the parental strain, mutants of each gene showed a significant reduction in their invasion capabilities. In addition, GEC cytoskeletal responses to the mutants were distinct from those induced by the parent. In contrast, adhesion of the mutant strains to GECs was not affected by lack of expression of the gene products. These results suggest that PepO, a cation-transporting ATPase, and an ABC transporter are required for the intracellular lifestyle of P. gingivalis.
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Katz, Jannet, Vijaya Sambandam, John H. Wu, Suzanne M. Michalek, and Daniel F. Balkovetz. "Characterization of Porphyromonas gingivalis-Induced Degradation of Epithelial Cell Junctional Complexes." Infection and Immunity 68, no. 3 (March 1, 2000): 1441–49. http://dx.doi.org/10.1128/iai.68.3.1441-1449.2000.
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ABSTRACT Porphyromonas gingivalis is considered among the etiological agents of human adult periodontitis. Although in vitro studies have shown that P. gingivalis has the ability to invade epithelial cell lines, its effect on the epithelial barrier junctions is not known. Immunofluorescence analysis of human gingival epithelial cells confirmed the presence of tight-junction (occludin), adherens junction (E-cadherin), and cell-extracellular matrix junction (β1-integrin) transmembrane proteins. These transmembrane proteins are expressed in Madin-Darby canine kidney (MDCK) cells. In addition, MDCK cells polarize and therefore serve as a useful in vitro model for studies on the epithelial cell barrier. Using the MDCK cell system, we examined the effect of P. gingivalis on epithelial barrier function. Exposure of the basolateral surfaces of MDCK cells to P. gingivalis (>109 bacteria/ml) resulted in a decrease in transepithelial resistance. Immunofluorescence microscopy demonstrated decreases in the amounts of immunoreactive occludin, E-cadherin, and β1-integrin at specific times which were related to a disruption of cell-cell junctions in MDCK cells exposed to basolateralP. gingivalis. Disruption of cell-cell junctions was also observed upon apical exposure to bacteria; however, the effects took longer than those seen upon basolateral exposure. Cell viability was not affected by either basolateral or apical exposure to P. gingivalis. Western blot analysis demonstrated hydrolysis of occludin, E-cadherin, and β1-integrin in lysates derived from MDCK cells exposed to P. gingivalis. Immunoprecipitated occludin and E-cadherin molecules from MDCK cell lysates were also degraded by P. gingivalis, suggesting a bacterial protease(s) capable of cleaving these epithelial junction transmembrane proteins. Collectively, these data suggest thatP. gingivalis is able to invade the deeper structures of connective tissues via a paracellular pathway by degrading epithelial cell-cell junction complexes, thus allowing the spread of the bacterium. These results also indicate the importance of a critical threshold concentration of P. gingivalis to initiate epithelial barrier destruction.
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Yilmaz, Özlem, Thomas Jungas, Philippe Verbeke, and David M. Ojcius. "Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Contributes to Survival of Primary Epithelial Cells Infected with the Periodontal Pathogen Porphyromonas gingivalis." Infection and Immunity 72, no. 7 (July 2004): 3743–51. http://dx.doi.org/10.1128/iai.72.7.3743-3751.2004.
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ABSTRACT Porphyromonas gingivalis, an important periodontal pathogen, infects primary gingival epithelial cells (GECs). Despite the large number of bacteria that replicate inside the GECs, the host cell remains viable. We demonstrate that P. gingivalis triggers rapid and reversible surface phosphatidylserine exposure through a mechanism requiring caspase activation. However, after 1 day of infection, the bacteria no longer induce phosphatidylserine externalization and instead protect infected cells against apoptosis. Infection exerts its effect at the level of mitochondria, as P. gingivalis also blocks depolarization of the mitochondrial transmembrane potential and cytochrome c release. Interestingly, protein kinase B/Akt is phosphorylated during infection, which can be blocked with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Suppression of the PI3K/Akt pathway following staurosporine treatment results in mitochondrial-membrane depolarization, cytochrome c release, DNA fragmentation, and increased apoptosis of infected GECs. Thus, P. gingivalis stimulates early surface exposure of phosphatidylserine, which could downmodulate the inflammatory response, while also promoting host cell survival through the PI3K/Akt pathway.
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Grenier, Daniel, Sophie Roy, Fatiha Chandad, Pascale Plamondon, Masami Yoshioka, Koji Nakayama, and Denis Mayrand. "Effect of Inactivation of the Arg- and/or Lys-Gingipain Gene on Selected Virulence and Physiological Properties of Porphyromonas gingivalis." Infection and Immunity 71, no. 8 (August 2003): 4742–48. http://dx.doi.org/10.1128/iai.71.8.4742-4748.2003.
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ABSTRACT Proteolytic enzymes produced by Porphyromonas gingivalis are thought to play critical roles in the pathogenesis of periodontitis. The aim of this study was to investigate the effect of gingipain cysteine proteinase gene inactivation on selected pathological and physiological functions of P. gingivalis. Our results showed that Arg- and Lys-gingipain activities are critical components for the efficient growth of P. gingivalis in human serum. However, when the serum was supplemented with peptides provided as pancreatic casein hydrolysate, the gingipains did not appear to be essential for growth. The effect of gingipain gene inactivation on the susceptibility of P. gingivalis to serum bactericidal activity was investigated using standardized human serum. The wild-type strain, P. gingivalis ATCC 33277, was largely unaffected by the bactericidal activity of human serum complement. On the other hand, mutants lacking Arg-gingipain A, Arg-gingipain B, or Lys-gingipain activity were susceptible to complement. Since gingipains are mostly located on the outer membrane of P. gingivalis, inactivation of the genes for these enzymes may modify cell surface properties. We showed that gingipain-deficient mutants differed in their capacities to assimilate radiolabeled amino acids, cause hemolysis, express adhesins, hemagglutinate, and form biofilms. Lastly, the gingipains, more specifically Arg-gingipains, were responsible for causing major cell damage to human gingival fibroblasts. In conclusion, our study indicated that, in addition to being critical in the pathogenic process, gingipains may play a variety of physiological roles in P. gingivalis, including controlling the expression and/or processing of virulence factors. Mutations in gingipain genes thus give rise to pleiotropic effects.
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Brozovic, Suzana, Rashmita Sahoo, Shirish Barve, Hideki Shiba, Silvia Uriarte, Richard S. Blumberg, and Denis F. Kinane. "Porphyromonas gingivalis enhances FasL expression via up-regulation of NFκB-mediated gene transcription and induces apoptotic cell death in human gingival epithelial cells." Microbiology 152, no. 3 (March 1, 2006): 797–806. http://dx.doi.org/10.1099/mic.0.28472-0.
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The interaction between epithelial cells and micro-organisms is often a crucial initiating event in infectious diseases. Infection with Porphyromonas gingivalis, a Gram-negative anaerobe, is strongly associated with severe periodontal disease. This bacterium possesses an array of virulence factors, some of which can induce apoptosis. The tumour necrosis factor (TNF) receptor family is involved in the regulation of cellular homeostasis, cell surface molecules involved in phagocytosis, Fas ligand (L) expression and activation of the caspase cascade resulting in DNA fragmentation and cell blebbing. The current study examined the role of nuclear factor-κB (NFκB) in FasL-mediated apoptotic cell death in primary human gingival epithelial cells (HGEC) induced by heat-killed P. gingivalis, probably through TLR signalling pathways. A marked up-regulation of TLR2 and Fas–FasL was detected in HGEC stimulated with P. gingivalis. Activation of NFκB by P. gingivalis in HGEC was demonstrated by an NFκB promoter luciferase assay as well as by phosphorylation of p65 as detected by Western blotting. Activation of cleaved caspase-3 and caspase-8 resulted in apoptotic cell death of HGEC. The survival proteins c-IAP-1/c-IAP-2 were decreased in HGEC exposed to P. gingivalis. HGEC apoptosis induced by P. gingivalis was inhibited by an anti-human FasL monoclonal antibody. Blockade of NFκB by helenalin resulted in down-regulation of FasL whereas a caspase-8 inhibitor did not decrease FasL. Taken together, these studies show that P. gingivalis can induce epithelial cell apoptosis through Fas–FasL up-regulation and activation of caspase-3 and caspase-8.
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Behm, Christian, Alice Blufstein, Setareh Younes Abhari, Christoph Koch, Johannes Gahn, Christina Schäffer, Andreas Moritz, Xiaohui Rausch-Fan, and Oleh Andrukhov. "Response of Human Mesenchymal Stromal Cells from Periodontal Tissue to LPS Depends on the Purity but Not on the LPS Source." Mediators of Inflammation 2020 (July 2, 2020): 1–17. http://dx.doi.org/10.1155/2020/8704896.
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Human periodontal ligament stromal cells (hPDLSCs) and gingival mesenchymal stromal cells (hGMSCs) are resident mesenchymal stromal cells (MSCs) of the periodontal tissue. The lipopolysaccharide (LPS) from Porphyromonas gingivalis is structurally distinct from that of other Gram-negative bacteria, and earlier studies linked this structural difference to a distinct virulence activity and the ability to activate toll-like receptor 2 (TLR-2), besides TLR-4 as commonly occurring upon LPS challenge. Later studies, in contrast, argue that TLR-2 activation by P. gingivalis LPS is due to lipoprotein contamination. In the present study, we aimed to define the influence of structure versus purity of P. gingivalis LPS on the immune response of hPDLSCs and hGMSCs. Cells were stimulated with commercially available “standard” P. gingivalis LPS, “ultrapure” P. gingivalis LPS, or “ultrapure” Escherichia coli LPS, and the expression of interleukin- (IL-) 8, IL-6, monocyte chemoattractant protein- (MCP-) 1, TLR-2, and TLR-4 was evaluated. The contribution of TLR-4 to the LPS-induced response was assessed using the specific TLR-4 inhibitor TAK-242. “Standard” P. gingivalis LPS induced significantly higher IL-8, IL-6, and MCP-1 production compared to the “ultrapure” LPS preparations, with no significant difference detectable for “ultrapure” LPS from P. gingivalis and E. coli. By using TAK-242, the response of hPDLSCs and hGMSCs to “ultrapure” LPS preparations was effectively inhibited to the levels comparable to those of nonstimulated controls. In contrast, high levels of response to “standard” LPS were observed, even in the presence of TAK-242. Our data show that the response of MSCs from periodontal tissue to LPS depends more on the purity of the LPS preparation than on the LPS source. Even a small amount of contaminating lipoproteins can drastically enhance the hPDLSCs’ and hGMSCs; responsiveness to P. gingivalis LPS, which might also contribute to the progression of periodontal disease.
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Ramamurthy, N. S., K. L. Schroeder, T. F. McNamara, A. J. Gwinnett, R. T. Evans, C. Bosko, and L. M. Golub. "Root-Surface Caries in Rats and Humans: Inhibition by a Non-Antimicrobial Property of Tetracyclines." Advances in Dental Research 12, no. 1 (November 1998): 43–50. http://dx.doi.org/10.1177/08959374980120011801.
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The incidence of root caries has been found to increase as the population ages and as edentulism becomes less prevalent due to improved dental awareness and care, and as exposure of roots due to gingival recession has also increased in the elderly. The mechanism of root caries is thought to be mediated by both bacterial and mammalian proteases produced by plaque and the periodontal tissues, respectively. In the current study, a rat model of periodontal disease was used in which gnotobiotic rats were infected intra-orally with a periodontal pathogen ( P. gingivalis). Infecting the rats with P. gingivalis increased the collagenase activity in the gingival tissue in association with severe alveolar bone loss. Treating P. gingivalis-infected rats with doxycycline or CMT-1 prevented the destruction of the periodontium by MMPs, thus preventing exposure of roots to subgingival bacterial plaque and host tissue collagenases and the subsequent development of root caries. In addition, a low-dose doxycycline (LDD, 20 mg bid, non-antimicrobial dose) for 3 months was used in humans predisposed to increased root caries as the result of heavy use of smokeless (chewing) tobacco, causing gingival recession, subgingival plaque accumulation with Gram-negative bacteria, increased gingival crevicular fluid flow (GCF), and elevated GCF collagenase. Daily administration of LDD in smokeless tobacco patients reduced the GCF collagenase and prevented the further development of root caries.
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Ramos Perfecto, Donald, Hilda Moromi Nakata, and Elba Martínez Cadillo. "Porphyromonas gingivalis:patógeno predominante en la periodontitis crónica." Odontología Sanmarquina 14, no. 1 (May 14, 2014): 34. http://dx.doi.org/10.15381/os.v14i1.2907.
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Porphyromonas gingivales es un bacilo gram negativo predominante en la Periodontitis crónica, sus múltiples factores de virulencia la hacen sumamente agresiva. En el surco gingival encuentra las condiciones para su crecimiento, interaccionando con el huésped produciendo una destrucción lenta pero constante de los tejidos del periodonto. Su predominancia ha sido considerada como un factor de riesgos para enfermedades sistémicas inflamatorios, como la del infarto de miocardio. Aunque su susceptibilidad a una diversidad de fármacos hace posible su manejo con antimicrobianos previa remoción mecánica de biofilm subgingival. En conclusión la revisión abarca diversas características de la bacteria, que nos unen al consenso de que Porphyromonas gingivalis es el patógeno de mayor relevancia en la periodontitis crónica, así como su presencia en diversas formas de patologías periodontales.
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Lamont, Richard J., and Howard F. Jenkinson. "Life Below the Gum Line: Pathogenic Mechanisms ofPorphyromonas gingivalis." Microbiology and Molecular Biology Reviews 62, no. 4 (December 1, 1998): 1244–63. http://dx.doi.org/10.1128/mmbr.62.4.1244-1263.1998.
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SUMMARY Porphyromonas gingivalis, a gram-negative anaerobe, is a major etiological agent in the initiation and progression of severe forms of periodontal disease. An opportunistic pathogen, P. gingivalis can also exist in commensal harmony with the host, with disease episodes ensuing from a shift in the ecological balance within the complex periodontal microenvironment. Colonization of the subgingival region is facilitated by the ability to adhere to available substrates such as adsorbed salivary molecules, matrix proteins, epithelial cells, and bacteria that are already established as a biofilm on tooth and epithelial surfaces. Binding to all of these substrates may be mediated by various regions of P. gingivalis fimbrillin, the structural subunit of the major fimbriae. P. gingivalis is an asaccharolytic organism, with a requirement for hemin (as a source of iron) and peptides for growth. At least three hemagglutinins and five proteinases are produced to satisfy these requirements. The hemagglutinin and proteinase genes contain extensive regions of highly conserved sequences, with posttranslational processing of proteinase gene products contributing to the formation of multimeric surface protein-adhesin complexes. Many of the virulence properties of P. gingivalis appear to be consequent to its adaptations to obtain hemin and peptides. Thus, hemagglutinins participate in adherence interactions with host cells, while proteinases contribute to inactivation of the effector molecules of the immune response and to tissue destruction. In addition to direct assault on the periodontal tissues, P. gingivalis can modulate eucaryotic cell signal transduction pathways, directing its uptake by gingival epithelial cells. Within this privileged site, P. gingivalis can replicate and impinge upon components of the innate host defense. Although a variety of surface molecules stimulate production of cytokines and other participants in the immune response, P. gingivalis may also undertake a stealth role whereby pivotal immune mediators are selectively inactivated. In keeping with its strict metabolic requirements, regulation of gene expression in P. gingivalis can be controlled at the transcriptional level. Finally, although periodontal disease is localized to the tissues surrounding the tooth, evidence is accumulating that infection with P. gingivalis may predispose to more serious systemic conditions such as cardiovascular disease and to delivery of preterm infants.
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Dommisch, Henrik, Whasun O. Chung, Maryam G. Rohani, David Williams, Minnie Rangarajan, Mike A. Curtis, and Beverly A. Dale. "Protease-Activated Receptor 2 Mediates Human Beta-Defensin 2 and CC Chemokine Ligand 20 mRNA Expression in Response to Proteases Secreted by Porphyromonas gingivalis." Infection and Immunity 75, no. 9 (June 25, 2007): 4326–33. http://dx.doi.org/10.1128/iai.00455-07.
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ABSTRACT The oral pathogen Porphyromonas gingivalis secretes proteases such as Arg-gingipain B (RgpB) that activate protease-activated receptors (PARs). Human beta-defensins (hBDs) and the macrophage inflammatory protein 3α/CC chemokine ligand 20 (CCL20) produced by epithelial cells are antimicrobial peptides that provide cytokine function and play an important role in innate immunity. The aim of the present study was to determine whether specific members of the PAR family mediate the expression of these innate immunity markers in gingival epithelial cells (GECs) when exposed to P. gingivalis cell-free culture supernatant or purified RgpB. hBD-2 mRNA in GECs was induced in response to supernatant and purified RgpB from P. gingivalis (P = 0.02 and P = 0.016, respectively). This effect was abrogated by the protease inhibitor tosyl-l-lysine chloromethyl ketone (TLCK) (P < 0.05). In response to P. gingivalis supernatant and to purified RgpB, the hBD-2 mRNA expression was significantly decreased in PAR-2 gene knockdown cells, whereas no change was detected in PAR-1 gene knockdown cells. CCL20 mRNA expression also increased in response to the supernatant of P. gingivalis, and this effect was blocked by the protease inhibitor, TLCK (P = 0.05 and P = 0.024, respectively), and was blocked in PAR-2 gene knockdown cells. Our data indicate that hBD-2 and CCL20 mRNA up-regulation by P. gingivalis supernatant and purified RgpB was mediated via PAR-2, but not via PAR-1, and that proteases play a role in the regulation of innate immune responses in GECs. GECs use PARs to recognize P. gingivalis and mediate cell responses involved in innate immunity.