EPSTEIN-BARR VIRUS ENCODED DUTPASE CONTAINING EXOSOMES MODULATE INNATE AND ADAPTIVE IMMUNE RESPONSES IN HUMAN DENDRITIC CELLS AND PERIPHERAL BLOOD MONONUCLEAR CELLS.
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-KB 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-KB activation and cytokine secretion in primary DCs and peripheral blood mononuclear cells (PBMCs). Interestingly, the production of proinflammatory 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.
Apoptosis/proliferation pathways, CCL20, cell cycle, DC-100, exosome formation, IL-10, IL12p40, IL12p70, IL-17, IL-1b, IL-23, IL-6, inflammation, Interferon Inducible Genes, Microarray gene analysis, oncogenesis, RANTES, TGF-a, TH1 cytokines, TH17 cytokines, TNF-a, Toll-like receptor signaling, viral defense
Deoxyuridine triphosphate nucleotidohydrolase, Epstein-Barr virus, Pam3csk4
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