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Bacterial Fimbriae Stimulate Proinflammatory Activation in the Endothelium through Distinct TLRs¹

Michael Davey^*,, Xinyan Liu^*, Takashi Ukai^2,*, Vishal Jain, Cynthia Gudino^*, Frank C. Gibson, III, Douglas Golenbock, Alberto Visintin and Caroline A. Genco^3,*,,¶

^* Section of Molecular Medicine and Section of Infectious Diseases, Department of Medicine, School of Medicine, Boston University, Boston, MA 02118; Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA 02118; Section of Infectious Diseases, Department of Medicine, School of Medicine, University of Massachusetts, Worcester, MA 01655; and ^¶ Department of Microbiology, School of Medicine, Boston University, Boston, MA 02118

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 K_d 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1-HL-080387 (to C.A.G.).

² Current address: Department of Periodontology, Unit of Translational Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.

³ Address correspondence and reprint requests to Dr. Caroline A. Genco, Section of Molecular Medicine, Department of Medicine, School of Medicine, Boston University, 650 Albany Street, Boston, MA 02118. E-mail address: cgenco{at}bu.edu

⁴ Abbreviations used in this paper: HAEC, human aortic endothelial cell; WT, wild type; dn, dominant negative; HA, hemagglutinin.

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