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Infection and Immunity, October 2006, p. 5658-5666, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00784-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Porphyromonas gingivalis Fimbriae Proactively Modulate ß2 Integrin Adhesive Activity and Promote Binding to and Internalization by Macrophages

George Hajishengallis,1,2,3* Min Wang,1,2 Evlambia Harokopakis,1,4 Martha Triantafilou,5 and Kathy Triantafilou5

Center for Oral Health and Systemic Disease,1 Departments of Periodontics,2 Immunology/Microbiology,3 Pedodontics, University of Louisville Health Sciences Center, Louisville, Kentucky 40292,4 Infection and Immunity Group, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, United Kingdom5

Received 16 May 2006/ Returned for modification 17 June 2006/ Accepted 12 July 2006

In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the ß2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this "inside-out" proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-ß-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates ß2 integrin adhesive activity for intracellular uptake.

* Corresponding author. Mailing address: University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292. Phone: (502) 852-5276. Fax: (502) 852-4052. E-mail: g0haji01{at}louisville.edu.

Editor: J. T. Barbieri

Infection and Immunity, October 2006, p. 5658-5666, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00784-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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