Porphyromonas gingivalis virulence factors involved in subversion of leukocytes and microbial dysbiosis.
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ABSTRACT:
SUBMITTER: Zenobia C
PROVIDER: S-EPMC4601496 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Purpose of reviewThis review summarizes mechanisms by which Porphyromonas gingivalis interacts with community members and the host so that it can persist in the periodontium under inflammatory conditions that drive periodontal disease.Recent findingsRecent advances indicate that, in great part, the pathogenicity of P. gingivalis is dependent upon its ability to establish residence in the subgingival environment and to subvert innate immunity in a manner that uncouples the nutritionally favorable (for the bacteria) inflammatory response from antimicrobial pathways. While the initial establishment of P. gingivalis is dependent upon interactions with early colonizing bacteria, the immune subversion strategies of P. gingivalis in turn benefit co-habiting species.SummarySpecific interspecies interactions and subversion of the host response contribute to the emergence and persistence of dysbiotic communities and are thus targets of therapeutic approaches for the treatment of periodontitis.
| S-EPMC7747940 | biostudies-literature
Project description:A 0.9-kb open reading frame encoding a unique 32-kDa protein was identified downstream of the recA gene of Porphyromonas gingivalis. Reverse transcription-PCR and Northern blot analysis showed that both the recA gene and this open reading frame are part of the same transcriptional unit. This cloned fragment was insertionally inactivated using the ermF-ermAM antibiotic resistance cassette to create a defective mutant by allelic exchange. When plated on Brucella blood agar, the mutant strain, designated P. gingivalis FLL92, was non-black pigmented and showed significant reduction in beta-hemolysis compared with the parent strain, P. gingivalis W83. Arginine- and lysine-specific cysteine protease activities, which were mostly soluble, were approximately 90% lower than that of the parent strain. Expression of the rgpA, rgpB, and kgp protease genes was the same in P. gingivalis FLL92 as in the wild-type strain. In contrast to the parent strain, P. gingivalis FLL92 showed increased autoaggregration in addition to a significant reduction in hemagglutinating and hemolysin activities. In in vivo experiments using a mouse model, P. gingivalis FLL92 was dramatically less virulent than the parent strain. A molecular survey of this mutant and the parent strain using all known P. gingivalis insertion sequence elements as probes suggested that no intragenomic changes due to the movement of these elements have occurred in P. gingivalis FLL92. Taken together, these results suggest that the recA downstream gene, designated vimA (virulence-modulating gene), plays an important role in virulence modulation in P. gingivalis W83, possibly representing a novel posttranscriptional or translational regulation of virulence factors in P. gingivalis.
| S-EPMC97887 | biostudies-literature
Project description:BackgroundPorphyromonas gingivalis inhibits oral epithelial wound healing in vitro more strongly than other oral bacteria, but it is unknown why P. gingivalis is such a potent inhibitor of wound healing.ObjectiveTherefore, the aim of this study was to investigate the influence of major virulence factors of P. gingivalis on wound healing in an in vitro wound-healing model. The influence of the capsular polysaccharide, the Arg- and Lys- gingipains, the major fimbriae and lipopolysaccharide (LPS) was investigated.DesignA standardized scratch was made in a confluent layer of human oral epithelial cells HO-1-N-1. The epithelial cells were then challenged with different concentrations of several P. gingivalis wild-type strains and knockout mutants. Closure of the scratch was determined after 17 h and compared to control conditions without bacteria.ResultsThe P. gingivalis strains ATCC 33277, W83, and W50 significantly inhibited wound healing. The presence of a capsular polysaccharide lowered significantly the inhibition of epithelial cell migration, while gingipain activity significantly increased the inhibition of cell migration. LPS and the major fimbriae did not influence epithelial cell migration. None of the tested P. gingivalis strains completely prevented the inhibition of cell migration, suggesting that other characteristics of P. gingivalis also play a role in the inhibition of wound healing, and that further research is needed.ConclusionsThe capsular polysaccharide and the Arg- and Lys- gingipains of P. gingivalis influenced the capacity of P. gingivalis to hinder wound healing, while LPS and the major fimbriae had no effect.
| S-EPMC4491305 | biostudies-literature
Project description:We have previously shown that benzamidine-type compounds can inhibit the activity of arginine-specific cysteine proteinases (gingipains HRgpA and RgpB); well-known virulence factors of Porphyromonas gingivalis. They also hinder in vitro growth of this important periodontopathogenic bacterium. Apparently growth arrest is not associated with their ability to inhibit these proteases, because pentamidine, which is a 20-fold less efficient inhibitor of gingipain than 2,6-bis-(4-amidinobenzyl)-cyclohexanone (ACH), blocked P. gingivalis growth far more effectively. To identify targets for benzamidine-derived compounds other than Arg-gingipains, and to explain their bacteriostatic effects, P. gingivalis ATCC 33277 and P. gingivalis M5-1-2 (clinical isolate) cell extracts were subjected to affinity chromatography using a benzamidine-Sepharose column to identify proteins interacting with benzamidine. In addition to HRgpA and RgpB the analysis revealed heat-shock protein GroEL as another ligand for benzamidine. To better understand the effect of benzamidine-derived compounds on P. gingivalis, bacteria were exposed to benzamidine, pentamidine, ACH and heat, and the expression of gingipains and GroEL was determined. Exposure to heat and benzamidine-derived compounds caused significant increases in GroEL, at both the mRNA and protein levels. Interestingly, despite the fact that gingipains were shown to be the main virulence factors in a fertilized egg model of infection, mortality rates were strongly reduced, not only by ACH, but also by pentamidine, a relatively weak gingipain inhibitor. This effect may depend not only on gingipain inhibition but also on interaction of benzamidine derivatives with GroEL. Therefore these compounds may find use in supportive periodontitis treatment.
| S-EPMC3620930 | biostudies-literature
Project description:Periodontitis is a common intraoral infection and is inextricably linked to systemic diseases. Recently, the regulation between host immunologic response and periodontal pathogens has become a hotspot to explain the mechanism of periodontitis and related systemic diseases. Since Porphyromonas gingivalis (P. gingivalis) was proved as critical periodontal pathogen above all, researches focusing on the mechanism of its virulence factors have received extensive attention. Studies have shown that in the development of periodontitis, in addition to the direct release of virulent factors by periodontal pathogens to destroy periodontal tissues, over-low or over-high intrinsic immune and inflammatory response mediated by Toll-like receptors (TLRs) can lead to more lasting destruction of periodontal tissues. It is very necessary to sort out how various cytopathic factors of P. gingivalis mediate inflammation and immune responses between the host through TLRs so as to help precisely prevent, diagnose, and treat periodontitis in clinic. This review summarizes the role of three most widely studied pathogenic factors produced by P. gingivalis (lipopolysaccharide, gingipains, pili) and their interactions with TLRs at the cellular and molecular level in the progress of periodontitis.
| S-EPMC6657652 | biostudies-literature
Project description:The main etiological agent of periodontitis is the anaerobic bacterium Porphyromonas gingivalis. Virulence of this pathogen is controlled by various mechanisms and executed by major virulence factors including the gingipain proteases, peptidylarginine deiminase (PPAD), and RagB, an outer membrane macromolecular transport component. Although the structures and functions of these proteins are well characterized, little is known about their posttranslational maturation. Here, we determined the phosphoproteome of P. gingivalis in which phosphorylated tyrosine residues constitute over 80% of all phosphoresidues. Multiple phosphotyrosines were found in gingipains, PPAD, and RagB. Although mutation of phosphorylated residues in PPAD and RagB had no effect on secretion or activity, site-directed mutagenesis showed that phosphorylation in hemagglutinin/adhesin domains of RgpA and Kgp, and in the catalytic domain of RgpB, had a strong influence on secretion, processing, and enzymatic activity. Moreover, preventing phosphorylation of one gingipain influenced the others, suggesting multiple phosphorylation-dependent pathways of gingipain maturation in P. gingivalis. Various candidate kinases including Ptk1 BY kinase and ubiquitous bacterial kinase 1 (UbK1) may be involved, but their contribution to gingipain processing and activation remains to be confirmed.
| S-EPMC10148667 | biostudies-literature
Project description:BACKGROUND:Periodontitis is recognized as a complex polymicrobial disease, however, the impact of the bacterial interactions among the 700-1,000 different species of the oral microbiota remains poorly understood. We conducted an in vitro screen for oral bacteria that mitigate selected virulence phenotypes of the important periodontal pathogen, Porphyromonas gingivalis. METHOD:We isolated and identified oral anaerobic bacteria from subgingival plaque of dental patients. When cocultured with P. gingivalis W83, specific isolates reduced the cytopathogenic effects of P. gingivalis on oral epithelial cells. RESULT:In an initial screen of 103 subgingival isolates, we identified 19 distinct strains from nine species of bacteria (including Actinomyces naeslundii, Streptococcus oralis, Streptococcus mitis, and Veilonella dispar) that protect oral epithelial cells from P. gingivalis-induced cytotoxicity. We found that some of these strains inhibited P. gingivalis growth in plate assays through the production of organic acids, whereas some decreased the gingipain activity of P. gingivalis in coculture or mixing experiments. CONCLUSION:In summary, we identified 19 strains isolated from human subgingival plaque that interacted with P. gingivalis, resulting in mitigation of its cytotoxicity to oral epithelial cells, inhibition of growth, and/or reduction of gingipain activity. Understanding the mechanisms of interaction between bacteria in the oral microbial community may lead to the development of new probiotic agents and new strategies for interrupting the development of periodontal disease.
| S-EPMC3198504 | biostudies-literature
Project description:The Porphyromonas gingivalis recombinant VimA can interact with the gingipains and several other proteins, including a sialidase. Sialylation can be involved in protein maturation; however, its role in virulence regulation in P. gingivalis is unknown. The three sialidase-related proteins in P. gingivalis showed the characteristic sialidase Asp signature motif (SXDXGXTW) and other unique domains. To evaluate the roles of the associated genes, randomly chosen P. gingivalis isogenic mutants created by allelic exchange and designated FLL401 (PG0778::ermF), FLL402 (PG1724::ermF), and FLL403 (PG0352::ermF-ermAM) were characterized. Similar to the wild-type strain, FLL402 and FLL403 displayed a black-pigmented phenotype in contrast to FLL401, which was not black pigmented. Sialidase activity in P. gingivalis FLL401 was reduced by approximately 70% in comparison to those in FLL402 and FLL403, which were reduced by approximately 42% and 5%, respectively. Although there were no changes in the expression of the gingipain genes, their activities were reduced by 60 to 90% in all the isogenic mutants compared to that for the wild type. Immunoreactive bands representing the catalytic domains for RgpA, RgpB, and Kgp were present in FLL402 and FLL403 but were missing in FLL401. While adhesion was decreased, the capacity for invasion of epithelial cells by the isogenic mutants was increased by 11 to 16% over that of the wild-type strain. Isogenic mutants defective in PG0778 and PG0352 were more sensitive to hydrogen peroxide than the wild type. Taken together, these results suggest that the P. gingivalis sialidase activity may be involved in regulating gingipain activity and other virulence factors and may be important in the pathogenesis of this organism.
| S-EPMC3191969 | biostudies-literature
Project description:Porphyromonas gingivalis, a black-pigmented, gram-negative anaerobe, is an important etiological agent of periodontal disease. Its ability to survive in the periodontal pocket and orchestrate the microbial/host activities that can lead to disease suggest that P. gingivalis possesses a complex regulatory network involving transcriptional and post-transcriptional mechanisms. The vimA (virulence modulating) gene is part of the 6.15-kb bcp-recA-vimA-vimE-vimF-aroG locus and plays a role in oxidative stress resistance. In addition to the glycosylation and anchorage of several surface proteins including the gingipains, VimA can also modulate sialylation, acetyl coenzyme A transfer, lipid A and its associated proteins and may be involved in protein sorting and transport. In this review, we examine the multifunctional role of VimA and discuss its possible involvement in a major regulatory network important for survival and virulence regulation in P. gingivalis. It is postulated that the multifunction of VimA is modulated via a post-translational mechanism involving acetylation.
| S-EPMC3625487 | biostudies-literature
Project description:Background: Porphyromonas gingivalis strain W83, one of the most widely investigated, is considered virulent in the context of periodontitis. The recently isolated P. gingivalis TDC60 has been reported to be highly pathogenic, although it has not yet been investigated in a mouse periodontitis model by oral gavage. Aim: Our aim was to compare the virulence of both strains by evaluating their impact on alveolar bone loss and the composition of oral microbiota. Methods: We inoculated by oral gavage C57BL/6 mice with either one of the two P. gingivalis strains and compared to a sham-treated group, without antibiotics pre-treatment. The mandibular alveolar bone of treated mice and controls were assessed, one month after the final inoculation, by microCT measurements. Moreover, at this time, we characterized their oral microbiota by 16S rRNA gene sequencing. Results: While P. gingivalis W83 successfully initiated periodontitis, TDC60-treated mice only experienced moderate lesions. Furthermore, only W83-treated mice exhibited a specific distinct microbiota, with significantly lower richness and evenness than other samples, and decreased proportions of taxa usually found in healthy individuals. Conclusion: This association between alveolar bone loss and a major persistent shift of the oral microbiota gives insights into virulence discrepancies among these bacterial strains.
| S-EPMC7580739 | biostudies-literature