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B through the TLR2 and MyD88-Dependent Signaling Pathway1
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* Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208;
Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, OH 43210;
Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210;
Institute for Behavioral Medicine Research, Ohio State University Medical Center, Columbus, OH 43210; and
¶ Department of Obstetrics and Gynecology, Ohio State University Medical Center, Columbus, OH 43210
The innate immune response plays a key role as the primary host defense against invading pathogens including viruses. We have previously shown that treatment of human monocyte-derived macrophages with EBV-encoded dUTPase induces the expression of proinflammatory cytokines through the activation of NF-
B. However, the receptor responsible for EBV-encoded dUTPase-mediated biological effects is not known. In this study, we demonstrate that the purified EBV-encoded dUTPase activates NF-B in a dose-dependent manner through TLR2 and requires the recruitment of the adaptor molecule MyD88 but not CD14. Furthermore, activation of NF-B was abrogated by anti-TLR2, anti-EBV-encoded dUTPase blocking Abs and the overexpression of a dominant negative construct of MyD88 in human embryonic kidney 293 cells expressing TLR2. In addition, treatment of human monocyte-derived macrophages with the anti-EBV-encoded dUTPase Ab 7D6 or the anti-TLR2 Ab blocked the production of IL-6 by the EBV-encoded dUTPase. To our knowledge, this is the first report demonstrating that a nonstructural protein encoded by EBV is a pathogen-associated molecular pattern and that it has immunomodulatory functions. Although additional studies are necessary to define the signaling pathways activated by the EBV-encoded dUTPase and to determine its role in modulating immune responses to EBV infection, our results suggest that the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by EBV.
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 work was supported in part by funds from the University of South Carolina Centenary Plan (to M.E.A.) and by Grants AG16321 and DE13749 (National Institutes of Health), The Gilbert and Kathryn Mitchell Endowment, and Ohio State University Comprehensive Cancer Center Core Grant CA16058 (to R.G.).
2 Address correspondence and reprint requests to Dr. Maria-Eugenia Ariza, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, 921 Assembly Street, Columbia, SC 29208. E-mail address: ariza{at}gwm.sc.edu
3 Abbreviations used in this paper: PAMP, pathogen-associated molecular patterns; PRR, pattern recognition receptor; Pam3Csk4, N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-(R)-Cys-(S)-Ser-(S)-Lys4 trihydrochloride; VZV, varicella-zoster virus; hCMV, human CMV; gp350, gp350/220; hMDM, human monocyte-derived macrophage; poly(IC), polyinosinic-polycytidylic acid; pAb, polyclonal Ab; NPC, nasopharyngeal carcinoma.
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