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J. Biol. Chem., Vol. 280, Issue 47, 38902-38913, November 25, 2005

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Peptide Mapping of Bacterial Fimbrial Epitopes Interacting with Pattern Recognition Receptors^*

From the Center of Excellence in Oral and Craniofacial Biology and Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70119

The fimbriae of the oral pathogen Porphyromonas gingivalis induce Toll-like receptor 2 (TLR2)-dependent macrophage activation upon their recognition by CD14 and the ₂ integrin CD11b/CD18. To map functional epitopes of fimbriae that interact with these pattern recognition receptors (PRRs), we examined 20 synthetic peptides covering the entire length of the 41-kDa fimbrillin subunit. Using direct or competitive inhibition assays for receptor binding or cell activation, the CD14 binding activity of fimbriae was localized to residues 69–90 and was essential for TLR2-dependent cytokine induction. The CD11b/CD18 binding activity of fimbriae was localized to two neighboring epitopes defined by residues 166–185 and 206–225. Unlike epitope 69–90 that constitutively bound CD14, the CD11b/CD18 binding activity of epitopes 166–185 and 206–225 was inducible by integrin activators. The CD11b/CD18 binding activity played a contributory role to TLR2-dependent induction of tumor necrosis factor- by fimbriae but was involved in specific down-regulation of interleukin-12. Cell activation by a combination of fimbrillin peptides corresponding to the CD14 and CD11b/CD18 binding activities resulted in higher tumor necrosis factor- responses than would be expected from a simply additive effect, attributable to CD14-dependent inside-out signaling leading to enhanced binding interactions with CD11b/CD18. These data suggest that P. gingivalis fimbriae display a modular structure that interacts through discrete epitopes and in a regulated mode with distinct PRRs, which in turn differentially modulate the state of cell activation. Elucidation of pathogen interactions with PRRs at the molecular level may glean insight into host defense mechanisms as well as into microbial strategies that subvert innate immunity.

Received for publication, July 6, 2005 , and in revised form, August 3, 2005.

^* This work was supported by United States Public Health Service Grant DE015254 from the NIDCR, National Institutes of Health. 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 To whom correspondence should be addressed: Oral Health and Systemic Disease Research Center, Dept. of Periodontics and Endodontics, University of Louisville School of Dentistry, Rm. 206, 501 S. Preston St., Louisville, KY 40202. Tel.: 502-852-5276; Fax: 502-852-4052; E-mail: g0haji01{at}louisville.edu.

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