Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral keratinocytes.
Primary infection of oral epithelial cells by HIV-1, if it occurs, could promote systemic infection. Most primary systemic infections are associated with R5-type HIV-1 targeting the R5-specific coreceptor CCR5, which is not usually expressed on oral keratinocytes. Because coinfection with other microbes has been suggested to modulate cellular infection by HIV-1, we hypothesized that oral keratinocytes may up-regulate CCR5 in response to the oral endogenous pathogen Porphyromonas gingivalis by cysteine-protease (gingipains) activation of the protease-activated receptors (PARs) or LPS signaling through the TLRs. The OKF6/TERT-2-immortalized normal human oral keratinocyte line expressed CXCR4, whereas CCR5 was not detectable. When exposed to P. gingivalis ATCC 33277, TERT-2 cells induced greater time-dependent expression of CCR5-specific mRNA and surface coreceptors than CXCR4. By comparing arg- (Rgp) and lys-gingipain (Kgp) mutants, a mutant deficient in both proteases, and the action of trypsin, P. gingivalis Rgp was strongly suggested to cleave PAR-1 and PAR-2 to up-regulate CCR5. CCR5 was also slightly up-regulated by an isogenic gingipain-deficient mutant, suggesting the presence of a nongingipain-mediated mechanism. Purified P. gingivalis LPS also up-regulated CCR5. Blocking TLR2 and TLR4 receptors with Abs attenuated induction of CCR5, suggesting LPS signaling through TLRs. P. gingivalis, therefore, selectively up-regulated CCR5 by two independent signaling pathways, Rgp acting on PAR-1 and PAR-2, and LPS on TLR2 and TLR4. By inducing CCR5 expression, P. gingivalis coinfection could promote selective R5-type HIV-1 infection of oral keratinocytes.
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
Rodrigo A
RA
Giacaman
Angela H
AH
Nobbs
Karen F
KF
Ross
Mark C
MC
Herzberg
D018829:Adhesins, Bacterial / Q000276:immunology / Q000378:metabolism; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D016866:Bacteroidaceae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009055:Mouth / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000276:immunology; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000276:immunology / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D018829:Adhesins, Bacterial; D000906:Antibodies; D000080867:Gingipain Cysteine Endopeptidases; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D003546:Cysteine Endopeptidases