EPSTEIN-BARR VIRUS ENCODED DUTPASE CONTAINING EXOSOMES MODULATE INNATE AND ADAPTIVE IMMUNE RESPONSES IN HUMAN DENDRITIC CELLS AND PERIPHERAL BLOOD MONONUCLEAR CELLS.

Ariza1,2, M.E., Rivailler3, P., Glaser1,2,4, R., Chen2, M.C., Williams1,2,4, M.V. 1Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America, 2Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, Ohio, United States of America, 3Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America, 4Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.

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-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.

Keywords

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

Materials Tested

Deoxyuridine triphosphate nucleotidohydrolase, Epstein-Barr virus, Pam3csk4

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