Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system.
Periodontitis is an inflammatory disease of the supporting structures of the teeth and is caused by, among other agents, Porphyromonas gingivalis. P. gingivalis is very resistant to killing by human complement, which is present in a gingival fluid at 70% of the serum concentration. We found that the incubation of human serum with purified cysteine proteases of P. gingivalis (gingipains) or P. gingivalis wild-type strains W83 and W50 resulted in a drastic decrease of the bactericidal activity of the serum. In contrast, serum treated with P. gingivalis mutants lacking gingipains (particularly strains without HRgpA) maintained significant bactericidal activity. To understand in detail the mechanism by which gingipains destroy the serum bactericidal activity, we investigated the effects of gingipains on the human complement system. We found that all three proteases degraded multiple complement components, with arginine-specific gingipains (HRgpA and RgpB) being more efficient than lysine-specific gingipain (Kgp). Interestingly, all three proteases at certain concentrations were able to activate the C1 complex in serum, which resulted in the deposition of C1q on inert surfaces and on bacteria themselves. It is therefore plausible that P. gingivalis activates complement when present at low numbers, resulting in a local inflammatory reaction and providing the bacteria with a colonization opportunity and nutrients. At later stages of infection the concentration of proteases is high enough to destroy complement factors and thus render the bacteria resistant to the bactericidal activity of complement.
Popadiak
Katarzyna
K
Lund University, Department of Laboratory Medicine, Section of Medical Protein Chemistry, University Hospital Malmö, Malmö, Sweden.
Potempa
Jan
J
Riesbeck
Kristian
K
Blom
Anna M
AM
D018829:Adhesins, Bacterial / Q000502:physiology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001770:Blood Bactericidal Activity / Q000276:immunology; D015922:Complement C1q / Q000378:metabolism; D003176:Complement C3 / Q000037:antagonists & inhibitors; D003181:Complement C4 / Q000037:antagonists & inhibitors; D003182:Complement C5 / Q000037:antagonists & inhibitors; D003169:Complement Inactivator Proteins / Q000502:physiology*; D003170:Complement Pathway, Alternative / Q000276:immunology; D003171:Complement Pathway, Classical / Q000276:immunology; D037582:Complement Pathway, Mannose-Binding Lectin / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000502:physiology*; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D016966:Porphyromonas gingivalis / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors
D018829:Adhesins, Bacterial; D000900:Anti-Bacterial Agents; D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D003169:Complement Inactivator Proteins; D000080867:Gingipain Cysteine Endopeptidases; D021122:Protein Subunits; D015922:Complement C1q; D003546:Cysteine Endopeptidases