The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway.
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-kappaB. 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-kappaB in a dose-dependent manner through TLR2 and requires the recruitment of the adaptor molecule MyD88 but not CD14. Furthermore, activation of NF-kappaB 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.
Ariza
Maria-Eugenia
ME
Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA. ariza@gwm.sc.edu
Glaser
Ronald
R
Kaumaya
Pravin T P
PT
Jones
Chris
C
Williams
Marshall V
MV
D002460:Cell Line; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology
D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014764:Viral Proteins; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase