PMID:23894549

Citation	Ariza, ME, Rivailler, P, Glaser, R, Chen, M and Williams, MV (2013) Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PLoS ONE 8:e69827
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.
Links	PubMed PMC3718799 Online version:10.1371/journal.pone.0069827
Keywords	Adaptive Immunity; Cell Line, Tumor; Cellular Microenvironment/immunology; Dendritic Cells/immunology; Dendritic Cells/metabolism; Dendritic Cells/secretion; Dendritic Cells/virology; Exosomes/secretion; Exosomes/virology; Herpesvirus 4, Human/physiology; Humans; Immunity, Innate; Leukocytes, Mononuclear/immunology; Leukocytes, Mononuclear/metabolism; Leukocytes, Mononuclear/secretion; Leukocytes, Mononuclear/virology; Pyrophosphatases/metabolism; Pyrophosphatases/secretion; Th1 Cells/immunology; Th1 Cells/secretion; Th17 Cells/immunology; Th17 Cells/secretion; Toll-Like Receptor 2/metabolism; Tumor Necrosis Factor-alpha/secretion
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
9CAUD:A0A0K2D093		GO:0004170: dUTP diphosphatase activity	ECO:0000314:		F		Gene Expression Analysis in Hdcs Quantitative Real-time PCR Western Blot Analysis Luciferase Reporter Gene Assays dUTPase Activity in Exosomes	complete CACAO 11461

References

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