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* Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455; and
Mucosal and Vaccine Research Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health/National Institute of Dental and Craniofacial Research R01DE015503.
2 R.A.G. is assistant professor on leave from the Departamento de Rehabilitacion Buco-maxilofacial, Facultad de Ciencias de la Salud, University of Talca, Talca, Chile.
3 Current address: Novartis Vaccines, Dipartimento di Biologia Molecolare, Via Fiorentina 1, 53100, Siena, Italy.
4 Address correspondence and reprint requests to Dr. Mark C. Herzberg, 17-164 Moos Tower, University of Minnesota, 515 Delaware Street, SE, Minneapolis, MN 55455. E-mail address: mcherzb{at}umn.edu
5 Abbreviations used in this paper: GI, gastrointestinal; PAR, protease-activated receptor; Kgp, lysine-specific or Lys-gingipain; Rgp, arginine-specific or Arg-gingipain; MOI, multiplicity of infection.
This article has been cited by other articles:
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  K. Imai, K. Ochiai, and T. Okamoto Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification J. Immunol., March 15, 2009; 182(6): 3688 - 3695. [Abstract] [Full Text] [PDF]
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 O. Yilmaz The chronicles of Porphyromonas gingivalis: the microbium, the human oral epithelium and their interplay Microbiology, October 1, 2008; 154(10): 2897 - 2903. [Abstract] [Full Text] [PDF]
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