Generation and degradation of the complement fragment C5a in human serum by <i>Bacteroides gingivalis</i>

Sundqvist, Göran; Bengtson, Ann; Carlsson, Jan

doi:10.1111/j.1399-302x.1988.tb00093.x

Cited by 32 publications

(24 citation statements)

References 31 publications

(37 reference statements)

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“…One of the first host defense mechanisms that P. gingivalis encounters is the complement system. The major complement factors C3 and C5 have been shown to be degraded by the gingipains in vitro into the biologically active components C3a and C5a [88,89]. C3a and C5a are both pro-inflammatory factors and C5a is a potent chemoattractant of phagocytic cells, especially neutrophils.…”

Section: Avoidance Of the Immune Response By P Gingivalis: Immunomentioning

confidence: 99%

Porphyromonas gingivalis Gingipains: The Molecular Teeth of a Microbial Vampire

O'Brien-Simpson

Veith²,

Dashper

et al. 2003

CPPS

156

177

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The gingipains are cell surface Arg- and Lys-specific proteinases of the bacterium Porphyromons gingivalis, which has been associated with periodontitis, a disease that results in the destruction of the teeth-s supporting tissues. The proteinases are encoded by three genes designated rgpA, rgpB and kgp. Arg-specific proteolytic activity is encoded by rgpA/B and the Lys-specific activity by kgp. RgpA and Kgp are polyproteins comprising proteinases with C-terminal adhesin domains that are proteolytically processed. After processing, the domains remain non-covalently associated as complexes on the cell surface. RgpB is also a cell surface proteinase but does not associate with adhesin domains. Using gene knockout P. gingivalis mutants, the proteolytic processing of the gingipain domains has been shown to involve the gingipains themselves as well as C-terminal processing by a carboxypeptidase. A motif in the C-terminal domain of each protein/polyprotein has been identified that is suggested to be involved in attachment to LPS on the cell surface. RgpB lacks a C-terminal adhesin binding motif found in the catalytic domains of RgpA and Kgp. This adhesin binding motif is proposed to be responsible for the non-covalent association of the RgpA and Kgp catalytic domains into the cell surface complexes with the processed adhesin domains. The RgpA-Kgp proteinase-adhesin complexes, through the adhesin domains A1 and A3, have been implicated in colonization of P. gingivalis by binding to other bacteria in subgingival plaque and also binding to crevicular epithelial cells. The RgpA-Kgp complexes also bind to fibrinogen, laminin, collagen type V, fibronectin and hemoglobin. Amino acid sequences likely to be involved in binding to these host proteins have been identified in adhesin domains A1 and A3. It is proposed that these adhesins target the proteolytic activity to host cell surface matrix proteins and receptors. The continual cycle of binding and degradation of the surface proteins/receptors on epithelial, fibroblast and endothelial cells by the RgpA-Kgp complexes in the gingival tissue leading to cell death would contribute to inflammation, tissue destruction and vascular disruption (bleeding). P. gingivalis has an obligate growth requirement for iron and protoporphyrin IX, which it preferentially utilizes in the form of hemoglobin. Kgp proteolytic activity is essential for rapid hydrolysis of hemoglobin and it is suggested therefore that a major role of the RgpA-Kgp complexes is in vascular disruption and the binding and rapid degradation of hemoglobin for heme assimilation by P. gingivalis. The RgpA-Kgp complexes also have a major role in the evasion and dysregulation of the host-s immune response. It is proposed that host pro-inflammatory cytokines and cellular receptors close to the infection site may be rapidly and efficiently degraded by the gingipains while the proteinases at lower concentrations distally could result in the promotion of an inflammatory response through activation of proteinase-activated receptors an...

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Section: Avoidance Of the Immune Response By P Gingivalis: Immunomentioning

confidence: 99%

Porphyromonas gingivalis Gingipains: The Molecular Teeth of a Microbial Vampire

O'Brien-Simpson

Veith²,

Dashper

et al. 2003

CPPS

156

177

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“…Proteolytic enzymes, which are produced in large quantity by this bacteria, are considered as important pathogenic agents (9-1 1 ). From a biochemical viewpoint, enzymes have been identified which hydrolyze complement factor CS (12,13), releasing a CSa-like neutrophil chemotactic fragment (14,15), which is likely to be involved in leukocyte infiltration of the gingiva. In addition, collagenases released (16,17) may contribute to the loss of periodontal attachment associated with progressive periodontal disease.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway.

Imamura¹,

Pike²,

Potempa³

et al. 1994

J. Clin. Invest.

169

128

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To elucidate the mechanism of production of an inflammatory exudate, gingival crevicular fluid (GCF), from periodontal pockets in periodontitis, we examined the vascular permeability enhancement (VPE) activity induced by an arginine-specific cysteine proteinase, Ar-gingipain-1 (RGP-1), produced by a major periopathogenic bacterium, Porphyromonas gingivalis. Intradermal injections into guinea pigs of RGP-1 (> 10' M), or human plasma incubated with RGP-1 (> 10-9 M), induced VPE in a dose-and activitydependent manner but with different time courses for the two routes of production. VPE activity induced by RGP-1 was augmented by kininase inhibitors, inhibited by a kallikrein inhibitor and unaffected by an antihistamine drug.The VPE activity in human plasma incubated with RGP-1 also correlated closely with generation of bradykinin (BK).RGP-1 induced 30-40% less VPE activity in Hageman factor-deficient plasma and no VPE in plasma deficient in either prekallikrein (PK) or high molecular weight kininogen (HMWK). After incubation with RGP-1, plasma deficient in PK or HMWK, reconstituted with each missing protein, caused VPE, as did a mixture of purified PK and HMVVK, but RGP-1 induced no VPE from HMWK. The VPE of extracts of clinically isolated P. gingivalis were reduced to about 10% by anti-RGP-1-IgG, leupeptin, or tosyl-L-lysine chloromethyl ketone, which paralleled effects observed with RGP-1. These results indicate that RGP-1 is the major VPE factor of P. gingivalis, inducing this activity through PK activation and subsequent BK release, resulting in GCF production at sites of periodontitis caused by infection with this organism. (J. Clin. Invest 1994. 94:361-367.)

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“…Plasma host defense and regulatory proteinase inhibitors ␣-antitrypsin, ␣ 2 -macroglobulin, antichymotrypsin, antithrombin III, and antiplasmin are also degraded by the P. gingivalis Arg and Lys proteinases (6). Inflammation at the site of infection may be enhanced by the Arg-and Lys-specific proteinases since the complement protein C5 has been reported to be hydrolyzed in vitro, releasing the biologically active C5a fragment (58). Cell lysis mediated by complement, however, may be avoided since the proteinases have been shown to degrade the other complement proteins (58,65).…”

mentioning

confidence: 99%

“…Inflammation at the site of infection may be enhanced by the Arg-and Lys-specific proteinases since the complement protein C5 has been reported to be hydrolyzed in vitro, releasing the biologically active C5a fragment (58). Cell lysis mediated by complement, however, may be avoided since the proteinases have been shown to degrade the other complement proteins (58,65). Phagocytic and other functions of recruited neutrophils to the inflamed site may also be impaired, since the proteinases are capable of degrading cell surface receptors (20,22).…”

mentioning

confidence: 99%

RgpA-Kgp Peptide-Based Immunogens Provide Protection againstPorphyromonas gingivalisChallenge in a Murine Lesion Model

2000

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Porphyromonas gingivalis, a gram-negative bacterium, has been linked to the onset and progression of periodontitis, a chronic inflammatory disease of the supporting tissues of the teeth. A major virulence factor of P. gingivalis is an extracellular complex of Arg-and Lys-specific proteinases and adhesins designated the RgpA-Kgp complex (formerly the PrtR-PrtK complex). In this study we show that the RgpA-Kgp complex, when used as an immunogen with incomplete Freund adjuvant (IFA), protects against challenge with invasive and noninvasive strains of P. gingivalis in the murine lesion model. We identified a variety of peptide vaccine candidates from the RgpA and Kgp polyprotein sequences that involved the putative active site histidine of both proteinases and five repeat motifs in the adhesin domains of both polyproteins implicated in aggregation and binding to host substrates, designated adhesin-binding motif (ABM) peptides. These peptides were synthesized using standard, solid-phase protocols for 9-fluorenylmethoxy carbonyl chemistry with S-acetylmercaptoacetic acid (SAMA) as the N-terminal residue. The SAMA-peptides were then conjugated to diphtheria toxoid and used with IFA to immunize BALB/c mice. Both active-site peptides and three of the five ABM peptides gave protection (P < 0.005) against challenge with P. gingivalis in the murine lesion model. The three ABM peptide sequences that conferred protection exist within a 100-residue span in the RgpA44 and Kgp39 adhesins of the RgpA-Kgp complex.

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Generation and degradation of the complement fragment C5a in human serum by Bacteroides gingivalis

Cited by 32 publications

References 31 publications

Porphyromonas gingivalis Gingipains: The Molecular Teeth of a Microbial Vampire

Porphyromonas gingivalis Gingipains: The Molecular Teeth of a Microbial Vampire

Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway.

RgpA-Kgp Peptide-Based Immunogens Provide Protection againstPorphyromonas gingivalisChallenge in a Murine Lesion Model

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