Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Hajishengallis, George Nikos
Complement; Porphyromonas gingivalis; Neutrophils
Gingivitis--Immunological aspects; Periodontal disease--Etiology
Complement, an early recognition system of innate immunity that senses local tissue damage and infection, cross-talks with and regulates other signaling systems, including Toll-like receptor (TLR) pathways. In the context of periodontitis, destructive inflammation and disease promotion are associated with extensive and synergistic activation of TLRs and complement within the chronically inflamed periodontium. The virulence of the periodontal pathogen Porphyromonas gingivalis is dependent, at least in part, upon its ability to use sophisticated stealth and sabotage tactics to undermine innate immunity. Intriguingly, although this pathogen can modulate TLR2 signaling and suppress specific aspects of complement activation (126), it proactively generates an active complement fragment (C5a) through limited degradation of the fifth complement component (C5) by virtue of its C5 convertase-like activity. We hypothesized that this seemingly counterproductive action may provide a survival advantage; permitting P. gingiva lis to instigate a subversive crosstalk between TLR2 and C5aR. Our work supports this hypothesis by demonstrating that C5a exposure promoted a synergistic rise of intracellular cAMP and impaired the ability of macrophages to destroy P. gingivalis. The cAMP synergy strictly required TLR2 signaling and a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, whereas protein kinase A and glycogen synthase kinase-3~ acted as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications in treating periodontal disease. This first demonstration of complementTLR crosstalk for immunosuppressive cAMP signaling indicates that pathogens may not simply undermine complement and/or TLRs as separate entities, but may also exploit their crosstalk pathways.
Krauss, Jennifer Lynn, "'Complementary' immune evasion by oral pathogen Porphyromonas gingivalis." (2010). Electronic Theses and Dissertations. Paper 776.