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.
Highlights
Epstein-Barr virus (EBV) is a gamma herpesvirus that is implicated in the pathogenesis of a variety of human malignancies including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), Hodgkin’s disease (HD), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, NK/T-cell lymphoma, and gastric carcinoma [1]
Previous studies performed in our laboratories demonstrated that EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase), an early protein produced during lytic replication of EBV, triggers a signaling cascade through TLR2 that results in the activation of NF-kB and increased secretion of pro-inflammatory cytokines [12]
We investigated whether the EBV-encoded dUTPase levels present in exosomes were sufficient to induce the secretion of cytokines in human DCs (hDCs) and peripheral blood mononuclear cells (PBMCs)
Summary
Epstein-Barr virus (EBV) is a gamma herpesvirus that is implicated in the pathogenesis of a variety of human malignancies including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), Hodgkin’s disease (HD), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, NK/T-cell lymphoma, and gastric carcinoma [1]. Given the importance of DCs in initiating an immune response against pathogens and the ability of EBV to establish persistent infections in the host, it might be expected that the virus has developed mechanism(s) to regulate the function of DCs as part of the virus strategy to evade immune surveillance. The interactions between DCs and EBV remain unclear and conflicting results have been reported concerning the ability of EBV to induce productive infections in DCs. Li et al [2] and Wang et al [3] reported that infection of monocytes by EBV results in apoptosis, preventing their differentiation into DCs. Walling et al [4] demonstrated that EBV established a latent infection in blood-borne mononuclear cells, which are precursors of Langerhans cells (LC) and that upon migration and differentiation into LC in the epithelium, EBV is reactivated establishing a productive (lytic) infection. These conflicting results suggest that while EBV may be able to infect monocytes, the effect of EBV on these cells varies with some precursors undergoing apoptosis, while infection of other precursors leads to the establishment of either a latent or productive infection
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