title: Mechanism and implications of CXCR4-mediated integrin activation by Porphyromonas gingivalis.
abstract: In monocytes and macrophages, the interaction of Porphyromonas gingivalis with Toll-like receptor 2 (TLR2) leads to the activation of a MyD88-dependent antimicrobial pathway and a phosphatidylinositol-3 kinase (PI3K) -dependent pro-adhesive pathway, which activates the β2 -integrin complement receptor 3 (CR3). By means of its fimbriae, P. gingivalis binds CXC-chemokine receptor 4 (CXCR4) and induces crosstalk with TLR2 that inhibits the MyD88-dependent antimicrobial pathway. In this paper, we investigated the impact of the P. gingivalis-CXCR4 interaction on the pro-adhesive pathway. Using human monocytes, mouse macrophages, or receptor-transfected cell lines, we showed that the binding of P. gingivalis fimbriae to CXCR4 induces CR3 activation via PI3K, albeit in a TLR2-independent manner. An isogenic strain of P. gingivalis expressing mutant fimbriae that do not interact with CXCR4 failed to efficiently activate CR3, leading to enhanced susceptibility to killing in vivo compared with the wild-type organism. This in vivo observation is consistent with previous findings that activated CR3 mediates safe entry of P. gingivalis into macrophages. Taken together with our previous work, these results indicate that the interaction of P. gingivalis with CXCR4 leads to inhibition of antimicrobial responses and enhancement of pro-adhesive responses, thereby maximizing its adaptive fitness in the mammalian host.
authors: Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA. geoh@dental.upenn.edu
authors: G
authors: G
authors: Hajishengallis
authors: M L
authors: ML
authors: McIntosh
authors: S-I
authors: SI
authors: Nishiyama
authors: F
authors: F
authors: Yoshimura
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology; D018829:Adhesins, Bacterial / Q000235:genetics / Q000276:immunology; D000818:Animals; D016866:Bacteroidaceae Infections / Q000276:immunology; D001596:Benzylamines; D018821:CD18 Antigens / Q000276:immunology*; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D000080027:Cyclams; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000276:immunology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016177:Macrophage-1 Antigen / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010795:Phthalic Acids / Q000494:pharmacology; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D020239:Receptor Cross-Talk / Q000276:immunology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018829:Adhesins, Bacterial; D001596:Benzylamines; D018821:CD18 Antigens; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016177:Macrophage-1 Antigen; D053594:Myeloid Differentiation Factor 88; D019869:Phosphatidylinositol 3-Kinases; D010795:Phthalic Acids; D019718:Receptors, CXCR4; D051195:Toll-Like Receptor 2; D015091:beta-Alanine; C546917:XVA 143; C088327:plerixafor
keywords: CXCR4; Porphyromonas gingivalis; Toll-like receptor 2; immune evasion; integrin; periodontitis