Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adhesins, Bacterial / immunology
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Adhesins, Bacterial / metabolism
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Antibodies / immunology
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Antibodies / pharmacology
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Bacteroidaceae Infections / genetics
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Bacteroidaceae Infections / immunology*
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Bacteroidaceae Infections / pathology
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Cell Line, Transformed
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Cysteine Endopeptidases / deficiency
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Cysteine Endopeptidases / immunology
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Cysteine Endopeptidases / metabolism
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Gingipain Cysteine Endopeptidases
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HIV Infections / genetics
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HIV Infections / immunology*
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HIV Infections / metabolism
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HIV Infections / pathology
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HIV-1 / immunology*
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HIV-1 / metabolism
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Humans
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Keratinocytes / immunology*
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Keratinocytes / metabolism
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Keratinocytes / pathology
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Lipopolysaccharides / pharmacology
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Mouth / immunology*
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Mouth / metabolism
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Mouth / pathology
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Mutation / immunology
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Porphyromonas gingivalis / genetics
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Porphyromonas gingivalis / immunology*
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Porphyromonas gingivalis / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, PAR-1 / immunology
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Receptor, PAR-1 / metabolism
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Receptor, PAR-2 / immunology
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Receptor, PAR-2 / metabolism
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Receptors, CCR5 / biosynthesis
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Receptors, CCR5 / immunology*
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Receptors, CXCR4 / biosynthesis
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / immunology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Up-Regulation / drug effects
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Up-Regulation / immunology*
Substances
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Adhesins, Bacterial
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Antibodies
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Gingipain Cysteine Endopeptidases
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Lipopolysaccharides
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RNA, Messenger
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Receptor, PAR-1
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Receptor, PAR-2
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Receptors, CCR5
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Receptors, CXCR4
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TLR2 protein, human
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TLR4 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Cysteine Endopeptidases