Porphyromonas gingivalis Gingipains: The Molecular Teeth of a Microbial Vampire

Abstract

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...

Macrophage Depletion Abates Porphyromonas gingivalis–Induced Alveolar Bone Resorption in Mice

“…This is consistent with other murine periodontitis studies in which IgG Abs were detected in mice infected with P. gingivalis, and no specific Ab was detected in uninoculated mice (48,73,86). Further, this is also consistent with human studies in which P. gingivalis-specific IgG Abs were detected in sera and gingival crevicular fluid from periodontitis patients, and the Ab titer correlated with disease severity (47,87). In both C57BL/6 and BALB/c mice, treatment with clodronate liposomes significantly reduced the specific Ab response to P. gingivalis.…”

“…The emergence of P. gingivalis in subgingival plaque and the release of one if its major virulence factors, the Arg-and Lys-specific cysteine proteinase-adhesin complexes (RgpA-Kgp complexes), into gingival tissue was suggested to be a major factor in inducing a chronic host inflammatory response, resulting in the cumulative tissue destruction and alveolar bone resorption observed in chronic periodontitis patients (5,(45)(46)(47)(48)(49)(50)(51). In addition to P. gingivalis proteins and LPS penetrating gingival tissue, P. gingivalis phosphorylated dihydoceramide lipids have been isolated from gingival tissue and subgingival plaque of chronic periodontitis patients (52)(53)(54).…”

The nucleoid-associated protein HUβ affects global gene expression in Porphyromonas gingivalis

“…In addition, the differential expression of a variety of DNA-binding proteins, including putative transcriptional repressors, sigma factors and NAPs was also of significance. These findings suggest that a complex regulatory network controls the ability of this 'microbial vampire' (O'Brien- Simpson et al, 2003) to acquire iron. Overall, our expression analysis studies show that HU plays a role in regulating a number of basic functions in P. gingivalis, such as growth, cell wall synthesis and iron acquisition under various growth conditions.…”

Treponema denticola chymotrypsin-like proteinase (CTLP) integrates spirochaetes within oral microbial communities

“…Since P. gingivalis produces several proteinases, e.g. RgpA (arginine-specific gingipain) and Kgp (lysine-specific gingipain), which degrade extracellular matrix (ECM) proteins and dysregulate host immune functions (O'Brien-Simpson et al, 2003;McAlister et al, 2009), it is envisaged that the concerted activities of P. gingivalis and T. denticola proteinases are highly disruptive to host tissues.…”