Role of bacterial proteinases in matrix destruction and modulation of host responses

Abstract

Recently accumulated large bodies of evidence have strongly implicated proteolytic enzymes released by subgingival plaque bacteria in the pathogenicity of periodontal disease. With regard to proteolytic power, however, the contribution from different microbial species considered as periodontal pathogens is not equal. Two of these bacteria, P. gingivalis and T. denticola, have developed an elaborate proteolytic systems composed of several surface-located or secreted enzymes, which apparently serve a role to provide bacteria with nutrients in the form of small peptides and amino acids. Of these two species, proteinases of P. gingivalis are the most intensively studied, and during the last decade an impressive array of information has been accumulated with respect to the biochemical characterization of purified proteinases and structure of the genes encoding them, the regulation of expression and the effects of these enzymes on host systems. In addition, studies on proteinase-deficient isogenic mutants has shed light on both their housekeeping functions and potential role(s) in the pathogenicity of periodontitis. Among several proteinases produced by P. gingivalis, the cysteine proteinases, referred to as gingipains, are clearly in the spotlight. They are the subject of several recent reviews and generally considered as the major virulence factors of this periodontal pathogen (59, 105, 139, 182, 183, 186, 281, 284, 286, 289). Gingipains seem to be key players in subverting host defense systems with, significantly, the complement and neutrophils being the main target. In addition, through uncontrolled activation of kallikrein/kinin pathway and coagulation cascade they contribute to local generation of bradykinin and thrombin, two synergistically working pro-inflammatory reagents with a strongly, although indirectly, stimulatory effect on bone resorption. Furthermore, the ability to interact with the cytokine networking systems has the potential to dysregulate the local inflammatory reaction. Finally, gingipains have a strong effect on mechanisms controlling host matrix metalloproteinase activity at the level of gene expression and zymogen activation (Fig. 10). Collectively, at the periodontal lesion site, the non-restrained action of gingipains, supported by other proteinases locally produced by subgingival plaque bacteria, would dysregulate most mechanisms controlling inflammatory reaction. Although successful in limiting infection to the periodontium, the ultimate effect of uncontrolled inflammatory processes would be the destruction of periodontal connective tissue, certainly the hallmark of periodontitis.

Effects of egg yolk antibody against Porphyromonas gingivalis gingipains in periodontitis patients

“…Arg-and Lys-cysteine proteinases (gingipains) are the main endopeptidases produced by P. gingivalis (7). Gingipains play a major role in the progression of human periodontal disease, especially in host colonization, inactivation of host defenses, tissue destruction, and host immune system modulation (8)(9)(10)(11)(12)(13)(14). In addition, gingipains play a role in bacterial housekeeping (15), including amino acid uptake from host proteins, heme acquisition from erythrocytes (16), and fimbriae maturation (17).…”

Purification and characterization of a clostripain-like protease from a recombinant Clostridium perfringens culture

“…its vascular permeability enhancement effect. A likely explanation for the effect is that Clp activates prekallikrein and releases bradykinin, as demonstrated for gingipains R (Potempa et al, 2000). The tissue swelling characteristic of clostridial myonecrosis may well be explained by this effect.…”

“…Arginine-specific gingipains R, RgpA and RgpB, and lysinespecific gingipain K contribute synergistically to the pathogenesis of P. gingivalis (Potempa et al, 2000;Tam et al, 2009;O'Brien-Simpson et al, 2009). Clp can hydrolyse Bz-DL-lysine pNA slightly but significantly, while Clo can only do so marginally.…”

Bacterial pathogenesis and mediators in apical periodontitis

“…Proteinases (or proteases) are enzymes either secreted extracellularly or expressed on the bacterial cell surface that are capable of hydrolyzing peptide bonds of proteins. They are candidates for contribution to the pathogenesis of apical periodontitis lesions through several mechanisms, including direct damage by degrading components of the extracellular matrix of the connective tissue; indirect damage by activating host matrix metalloproteinases; and subversion of the host defense mechanisms by inactivation of proteins such as immunoglobulins and complement components (60)(61)(62). For instance, bacteria with collagenase activity have been found more frequently in cases of large apical periodontitis lesions, which suggests that such enzyme activity may be contributory to the enlargement of the lesion (63).…”