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

Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13532-7. doi: 10.1073/pnas.0803852105. Epub 2008 Sep 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteroidaceae Infections / immunology
  • Cell Survival
  • Cells, Cultured
  • Cricetinae
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Fimbriae Proteins / immunology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Monocytes / immunology
  • NF-kappa B / metabolism
  • Nitrogen Oxides / metabolism
  • Porphyromonas gingivalis / immunology*
  • Porphyromonas gingivalis / pathogenicity*
  • Protein Binding
  • Receptor Cross-Talk / immunology*
  • Receptors, CXCR4 / immunology*
  • Toll-Like Receptor 2 / deficiency
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 2 / metabolism

Substances

  • NF-kappa B
  • Nitrogen Oxides
  • Receptors, CXCR4
  • Toll-Like Receptor 2
  • Fimbriae Proteins
  • Cyclic AMP-Dependent Protein Kinases