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PNAS 105 (36): 13532-13537

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function

George Hajishengallis*,{dagger},{ddagger}, Min Wang*, Shuang Liang*, Martha Triantafilou§, and Kathy Triantafilou§

*Division of Oral Health and Systemic Disease/Department of Periodontics and {dagger}Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292; and §Infection and Immunity Group, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, United Kingdom

Edited by Bruce Alan Beutler, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board July 2, 2008

Received for publication April 23, 2008.

Abstract: We report a mechanism of microbial evasion of Toll-like receptor (TLR)-mediated immunity that depends on CXCR4 exploitation. Specifically, the oral/systemic pathogen Porphyromonas gingivalis induces cross-talk between CXCR4 and TLR2 in human monocytes or mouse macrophages and undermines host defense. This is accomplished through its surface fimbriae, which induce CXCR4/TLR2 co-association in lipid rafts and interact with both receptors: Binding to CXCR4 induces cAMP-dependent protein kinase A (PKA) signaling, which in turn inhibits TLR2-mediated proinflammatory and antimicrobial responses to the pathogen. This outcome enables P. gingivalis to resist clearance in vitro and in vivo and thus to promote its adaptive fitness. However, a specific CXCR4 antagonist abrogates this immune evasion mechanism and offers a promising counterstrategy for the control of P. gingivalis periodontal or systemic infections.

Key Words: bacterial pathogenesis • immune evasion • macrophages • P. gingivalis • protein kinase A


Freely available online through the PNAS open access option.

Author contributions: G.H., M.T., and K.T. designed research; G.H., M.W., S.L., M.T., and K.T. performed research; G.H., M.W., S.L., M.T., and K.T. analyzed data; and G.H. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. B.A.B. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/cgi/content/full/0803852105/DCSupplemental.

{ddagger}To whom correspondence should be addressed at: University of Louisville, 501 South Preston Street, Louisville, KY 40292. E-mail: g0haji01{at}louisville.edu

© 2008 by The National Academy of Sciences of the USA


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