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Porphyromonas gingivalis outer membrane vesicles promote apoptosis via msRNA-regulated DNA methylation in periodontitis

ABSTRACT: The outer membrane vesicles (OMVs) produced by Porphyromonas gingivalis (P. gingivalis) contain a variety of bioactive molecules that may be involved in the progression of periodontitis. However, the participation of P. gingivalis OMVs in the development of periodontitis has not been elucidated. Here we isolated P. gingivalis OMVs and confirmed their participation in periodontitis both in vivo and in vitro. Microcomputed Tomography (micro-CT) and histological analysis showed that under the stimulation of P. gingivalis OMVs, the alveolar bone of rats was significantly resorbed in vivo. We found that P. gingivalis OMVs were taken up by hPDLCs (human Periodontal Ligament Cells, hPDLCs) in vitro, then subsequently resulting in apoptosis and inflammatory cytokines releasing which was accomplished by the microRNA-size small RNAs (msRNAs) sRNA45033 in the P. gingivalis OMVs. Through bioinformatics analysis and screening of target genes, Chromobox 5 (CBX5) was identified as the downstream target of screened-out small RNA s45033. Using dual-luciferase reporter assay, overexpression, and knockdown methods, s45033 was confirmed to target CBX5 to regulate hPDLCs apoptosis. In addition, Cleavage Under Targets and Tagmentation (Cut&Tag) analysis confirmed the mechanism that CBX5 regulates apoptosis through the methylation of p53 DNA. Collectively, these findings indicate that the role of P. gingivalis OMVs is immunologically relevant and related to bacterial virulence in the development of periodontitis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218606 | GEO | 2022/11/30

REPOSITORIES: GEO

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Porphyromonas gingivalis Outer Membrane Vesicle and cell Proteome in heme excess and heme limited

Project description:Porphyromonas gingivalis is an anaerobic, Gram-negative oral pathogen associated with chronic periodontitis. P. gingivalis has an obligate requirement for heme which it obtains from the host. Heme availability has been linked to disease initiation and progression. In this study we used continuous culture of the bacterium to determine the effect of heme limitation and excess on the P. gingivalis proteome. Four biological replicates of whole cell lysate (WCL) and outer membrane vesicle (OMV) samples were digested with trypsin and analysed by tandem mass spectrometry and MaxQuant label-free quantification. In total, 1211 proteins were quantified with 108 and 49 proteins significantly changing in abundance more than 1.5-fold (p<0.05) in the WCLs and OMVs respectively. The proteins most upregulated in response to heme limitation were those involved in binding and transporting heme while the four proteins most upregulated in the heme excess condition constitute a putative heme efflux system. In general, the protein abundance ratios obtained for OMVs and WCLs agreed, indicating that changes to the OM protein composition are passed on to OMVs, however 16 proteins were preferentially packaged into OMVs in one condition more than the other. In particular, moonlighting cytoplasmic proteins were preferentially associated with OMVs under heme excess.

2018-05-18 | PXD009730 | Pride

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2013-11-17 | E-MTAB-1922 | biostudies-arrayexpress

Polyphenols from Myrothamnus flabellifolia Welw. inhibit in vitro adhesion of Porphyromonas gingivalis and exert anti-inflammatory cytoprotective effects in KB cells

Project description:Investigation of whole genome gene expression level changes in Porphyromonas gingivalis ATCC 33277 treated with an anti-adhesive extract from Myrothamnus flabellifolia compared to the untreated strain. Aim: Identification of anti-adhesive plant extracts against cell surface binding of Porphyromonas gingivalis. Materials and Methods: Polyphenol-enriched extract from Myrothamnus flabellifolia (MF) traditionally used for periodontitis was tested for inhibition of P. gingivalis adhesion to KB cells by FACS, for influence on gingipain activity, hemagglutination and by microarray analysis for effects on the bacterial transcriptome. P. gingivalis-induced inflammation parameters were monitored by RT-PCR. Results: MF (100 µg/ml) reduced P. gingivalis adhesion/invasion about 50% by interacting with fimbriae and bacterial OMPs. Microarray analysis of MF-treated bacteria indicated up-regulation of genes involved in cell adhesion. As confirmed by RT-PCR, fimbrillin- and Arg-gingipain-encoding genes were upregulated by MF. On the protein level, inhibition (70%) of Arg-gingipain activity was observed, while the corresponding Lys-gingipain was hardly influenced. MF also inhibited hemagglutination. While exposure to P. gingivalis resulted in an increased expression of inflammation-related genes in KB cells, pretreatment of KB cells with MF evoked cytoprotective effects concerning IL-1β, IL-6, IL-8 and TNFα gene expression as well as IL-6 release rates. Conclusions: While being cytoprotective, MF exerts strong anti-adhesive effects against P. gingivalis. Thus, MF may be useful for the prevention of P. gingivalis-associated periodontal diseases. The chip study used total RNA recovered from two separate MF-treated and two separate untreated Porphyromonas gingivalis ATCC 33277 cultures. Each chip measured the expression level of 1,842 genes from P. gingivalis ATCC 33277 with thirteen 60-mer probes per gene, with three-fold technical redundancy.

2010-09-02 | E-GEOD-23939 | biostudies-arrayexpress

Coating and corruption of human neutrophils by bacterial outer membrane vesicles

Project description:Porphyromonas gingivalis is a keystone oral pathogen that successfully manipulates the human innate immune defenses, resulting in a chronic pro-inflammatory state of periodontal tissues and beyond. Here we demonstrate that secreted outer membrane vesicles (OMVs) are deployed by P. gingivalis to selectively coat and activate human neutrophils, thereby provoking degranulation without neutrophil killing. Secreted granule components with antibacterial activity, especially LL-37 and MPO, are subsequently degraded by potent OMV-bound proteases known as gingipains, thereby ensuring bacterial survival. In contrast to neutrophils, the P. gingivalis OMVs are efficiently internalized by macrophages and epithelial cells. Importantly, we show that neutrophil coating is a conserved feature displayed by OMVs of at least one other oral pathogen, namely Aggregatibacter actinomycetemcomitans. Altogether, we conclude that P. gingivalis deploys its OMVs for a neutrophil-deceptive strategy to escape phagocytosis and to create a favorable inflammatory niche.

2022-08-16 | PXD026704 | Pride

Polyphenols from Myrothamnus flabellifolia Welw. inhibit in vitro adhesion of Porphyromonas gingivalis and exert anti-inflammatory cytoprotective effects in KB cells

2010-09-02 | GSE23939 | GEO

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Project description:We report the study of the mechanism of action of Porphyromonas gingivalis on human oral epithelial cells based on high-throughput sequencing technology. By acting Porphyromonas gingivalis and its metabolites on human oral epithelial cells separately, the mechanism of Porphyromonas gingivalis evading immune surveillance and causing local and deep tissue diffusion to induce systemic diseases was studied. This study provides a framework for studying the pathogenic mechanism of Porphyromonas gingivalis.

2023-02-21 | GSE192887 | GEO

Characterization of the O-Glycoproteome of Prevotella intermedia

Project description:Prevotella intermedia is a Gram-negative bacterium belonging to the Bacteroidetes phylum and is notably linked to periodontitis. Several other species within this phylum have been reported to possess the general O-glycosylation system, and the O-glycoproteome has been well characterized in Tannerella forsythia, Porphyromonas gingivalis, and Flavobacterium johnsoniae. In this study, we used electron cryotomography (cryoET) to view the ultrastructure of P. intermedia for the first time, revealing an electron dense surface layer surrounding both cells and outer membrane vesicles (OMVs). Interestingly, the OMVs were frequently large (>200 nm) and were of two types, with the lumens being either electron dense or translucent. LC-MS/MS analyses of OMVs and various cell fractions of P. intermedia resulted in the identification of 1655 proteins including 62 predicted T9SS cargo proteins. Consistent with the presence of large OMVs with electron dense lumens, periplasmic proteins contributed to nearly half the protein content of OMVs. For the glycoproteome, 445 unique O-glycosylation sites within 226 glycoproteins were identified. The O-glycosylation motif exhibited a much broader range than reported in other species, with O-glycosylation found at D(S/T)(A/I/L/M/T/V/S/C/G/F/N/E/Q/D/P). A single major O-glycan was identified of delta mass 1531.48 Da and its sequence was determined by MS2 and MS3 analyses using a combination of CID and HCD fragmentation modes. Following partial deglycosylation with trifluoromethanesulfonic acid, the O-glycan sequence was confirmed to be dHex-dHex-HexNAc(HPO3-C6H12O5)-dHex-Hex-HexA-Hex(dHex). Bioinformatic analyses of O-glycoprotein localization predicted 73 periplasmic proteins, 53 inner membrane proteins, 52 lipoproteins, 26 outer membrane proteins, and 14 proteins secreted by the T9SS.

2024-02-14 | PXD047143 | Pride

membrane substrates of gingipains

Project description:Porphyromonas gingivalis secretes cysteine proteases named gingipains which can cleave an array of proteins and importantly contribute to the development of periodontitis. In this study we focused on gingipain-exerted proteolysis at the cell surface of human gingival epithelial cells (telomerase immortalized gingival keratinocytes [TIGK]). We examined whether gingipains have sheddase activity or if their main activity is degradation of membrane proteins into small fragments. Using mass spectrometry, we investigated the whole sheddome/degradome of TIGK cell surface proteins by P. gingivalis strains differing in gingipain expression. We observed extensive degradation of TIGK surface proteins, suggesting that gingipains could in fact be the major cause of damage to the gingival epithelium. Most of the identified gingipain substrates were molecules involved in adhesion, suggesting that gingipains may cause tissue damage through cleavage of cell contacts, resulting in cell detachment and rounding, and consequently leading to anoikis. These results reveal a molecular underpinning to P. gingivalis-induced tissue destruction and enhance our knowledge of the role of P. gingivalis’ proteases in the pathobiology of periodontitis.

2020-04-28 | PXD015679 | Pride

Changes in gut microbiota induced by oral pathobiont deteriorate the pathology of non-alcoholic fatty liver disease

Project description:Periodontitis increases the risk of non-alcoholic fatty liver disease (NAFLD). However, the precise mechanisms are unclear. Here, gut dysbiosis induced by orally administered Porphyromonas gingivalis, a representative periodontopathic bacterium, was implicated in the deterioration of NAFLD pathology. C57BL/6 mice were administered with the vehicle, P. gingivalis or Prevotella intermedia, with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, high fat diet (CDAHFD60). CDAHFD60 feeding induced hepatic steatosis, and combined bacterial administration further aggravated NAFLD pathology with increased fibrosis. Liver gene expression analyses revealed that genes involved in the NAFLD pathology were perturbed with distinctive expression profiles induced by different bacteria. These differences may be due to quantitative and qualitative differences in the influx of gut bacterial products because the serum endotoxin level, gut microbiota composition, and serum metabolite profile caused by ingested P. intermedia and P. gingivalis were different. These findings provide insights into mechanisms linking periodontitis and NAFLD.

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The influence of gingipains on latent capacity of B cells

Project description:Porphyromonas gingivalis (P. gingivalis) is a key pathogen in periodontitis. Our previous study indicated that periodontitis induced by P. gingivalis increases the percentage of CD19+ B cells, Th17, Treg, gMDSCs and mMDSCs but decreases the ratio of B10 cells in CIA mice. It’s unclear which virulence factors of P. gingivalis are involved in these processes. Here, our study first indicated that such effects are mainly resulted from the undenatured proteins other than the DNA, RNA or LPS of P. gingivalis. As gingipains are enzymes and virulence factors which play vital role in the progression in periodontitis through affecting innate and adaptive immune system, we then compared the influence of the wild-type strain of P. gingivalis (ATCC33277) with its isogenic gingipain-null mutant (△K△RAB) on B cells. The results showed that B cells infected with △K△RAB exhibited increased levels of IL-6 and others cytokines (IL-1β，IL-23) involve in Th17 differentiation compared to wild-type strain, also the frequency of IL-10 producing regulatory B cells (B10). Furthermore, the peritonitis induced by △K△RAB enhanced the proportion of B10 and Th17 compared with treated with ATCC33277. Cumulatively, this study preliminarily revealed deletion of gingipains affected the antigen presentation of B cell that promoted B cells express the cytokines which promoted T cells toward Th17 and the secretion immunosuppressive cytokines of B cells that enhanced the frequency of B10 which implicated gingipains are vital in altering B cell function to participated immune response.

2023-05-29 | GSE195704 | GEO

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