Bacterial Fimbriae Stimulate Proinflammatory Activation in the Endothelium through Distinct TLRs

Abstract

The major and minor fimbriae proteins produced by the human pathogen Porphyromonas gingivalis are required for invasion of human aortic endothelial cells and for the stimulation of potent inflammatory responses. In this study, we report that native forms of both the major and minor fimbriae proteins bind to and signal through TLR2 for this response. Major and minor fimbriae bound to a human TLR2:Fc chimeric protein with an observed Kd of 28.9 nM and 61.7 nM, respectively. Direct binding of the major and minor fimbriae to a human chimeric CD14-Fc protein also established specific binding of the major and minor fimbriae to CD14 with classic saturation kinetics. Using a P. gingivalis major and minor fimbriae mutant, we confirmed that TLR2 binding in whole cells is dependent on the expression of the major and minor fimbriae. Although we did not observe binding with the major or minor fimbriae to the TLR4-Fc chimeric protein, signaling through TLR4 for both proteins was demonstrated in human embryonic kidney 293 cells transfected with TLR4 and only in the presence MD-2. Transient transfection of dominant-negative forms of TLR2 or TLR4 reduced IL-8 production by human aortic endothelial cells following stimulation with major or minor fimbriae. The ability of two well-defined microbe-associated molecular patterns to select for innate immune recognition receptors based on accessory proteins may provide a novel way for a pathogen to sense and signal in appropriate host environments.

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

“…7 P. gingivalis features numerous intensely studied structural and secreted components capable of interacting with the host immune system. Among its virulence factors, fimbrial proteins bind to and trigger epithelial TLR2, 8 whereas P. gingivalis LPS activates TLR2-and/or TLR4-expressing cells. 9 -13 As a result of its unique structural and chemical properties, P. gingivalis LPS exhibits lower levels of endotoxic potency compared with classic enterobacterial preparations such as Escherichia coli LPS, perhaps because of lower binding affinity to host LPS-binding protein as well as its dual recognition by TLR2 and TLR4.…”

Mechanisms of Periodontitis - Induced Atherosclerosis

“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] PG�s fimbriae secretes protein, called gp130, [83] which facilitate PG to invade EC and trigger celluler immune response. [84] The host will secrete TNF, [85] IL-1, IL-6, IL-10, and IL-12 [86][87][88] by TLR�s stimulation. [26,85,[88][89][90] TLR is part of immune system, which will respond to PAMP.…”

“…[84] The host will secrete TNF, [85] IL-1, IL-6, IL-10, and IL-12 [86][87][88] by TLR�s stimulation. [26,85,[88][89][90] TLR is part of immune system, which will respond to PAMP. [91] Protein in PG�s fimbriae may act as PAMP which triggers immune response by activating TLR, which, hence stimulate the host to produce cytokines.…”

“…[92] Mechanism of PG infection and neointima thickening was remained unclear. It was supposed that TNF stimulation by protein gp130 [83] might facilitate lymphocyte and monocyte adhesion [85] and also stimulate cytokines and growth hormone in host cells. [86][87][88][89][90][91][92][93] Neointima formation is mainly caused by accelerating proliferation rate, inhibiting apoptotic process, and increasing SMC migration to the neointima layer.…”

Pathogenic and opportunistic respiratory bacteria-induced apoptosis

“…Second, the increased TLR2 expression will probably contribute to the accelerated immune response by epithelial cells as well as the resensitization of epithelial cells to invading pathogens. If so, tight regulation of TLR2 expression should be one of the important immune-regulatory mechanisms commonly involved in host defense against many bacterial strains [45]. Despite the extensive studies on the roles of TLR in host defense and immune response, how the expression of TLR during bacterial infections is tightly regulated still remains largely unknown.…”