title: Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells.
abstract: We have recently demonstrated that Epstein-Barr virus (EBV)-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) modulates innate immunity in human primary monocyte-derived macrophages through toll-like receptor (TLR) 2 leading to NF-κB activation and the production of pro-inflammatory cytokines. Our previous depletion studies indicated that dendritic cells (DCs) may also be a target of the EBV-encoded dUTPase. However, the role of EBV-encoded dUTPase in DC activation/function and its potential contribution to the inflammatory cellular milieu characteristic of EBV-associated diseases remains poorly understood. In the present study, we demonstrate that EBV-encoded dUTPase significantly altered the expression of genes involved in oncogenesis, inflammation and viral defense mechanisms in human primary DCs by microarray analysis. Proteome array studies revealed that EBV-encoded dUTPase modulates DC immune responses by inducing the secretion of pro-inflammatory TH1/TH17 cytokines. More importantly, we demonstrate that EBV-encoded dUTPase is secreted in exosomes from chemically induced Raji cells at sufficient levels to induce NF-κB activation and cytokine secretion in primary DCs and peripheral blood mononuclear cells (PBMCs). Interestingly, the production of pro-inflammatory cytokines in DCs and PBMCs was TLR2-dependent. Together these findings suggest that the EBV-encoded dUTPase may act as an intercellular signaling molecule capable of modulating the cellular microenvironment and thus, it may be important in the pathophysiology of EBV related diseases.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA. maria.ariza@osumc.edu
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Ariza
authors.forename: Pierre
authors.initials: P
authors.lastname: Rivailler
authors.forename: Ronald
authors.initials: R
authors.lastname: Glaser
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Marshall V
authors.initials: MV
authors.lastname: Williams
mesh_terms: D056704:Adaptive Immunity; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D055354:Exosomes / Q000378:metabolism* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D011755:Pyrophosphatases / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase
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