Epstein-Barr Virus-Encoded RNAs: Key Molecules in Viral Pathogenesis

Abstract

The Epstein-Barr virus (EBV) is known as an oncogenic herpesvirus that has been implicated in the pathogenesis of various malignancies. EBV-encoded RNAs (EBERs) are non-coding RNAs expressed abundantly in latently EBV-infected cells. Herein, I summarize the current understanding of the functions of EBERs, including the interactions with cellular factors through which EBERs contribute to EBV-mediated pathogenesis. Previous studies have demonstrated that EBERs are responsible for malignant phenotypes in lymphoid cells, and can induce several cytokines that can promote the growth of various EBV-infected cancer cells. EBERs were also found to bind retinoic acid-inducible gene I (RIG-I) and thus activate its downstream signaling. Furthermore, EBERs induce interleukin-10, an autocrine growth factor for Burkitt's lymphoma cells, by activating RIG-I/interferon regulatory factor 3 pathway, suggesting that EBER-mediated innate immune signaling modulation contributes to EBV-mediated oncogenesis. Recently, EBV-infected cells were reported to secret EBERs, which were then recognized by toll-like receptor 3 (TLR3), leading to the induction of type I interferon and inflammatory cytokines, and subsequent immune activation. Furthermore, EBER1 was detected in the sera of patients with active EBV-infectious diseases, suggesting that EBER1-meidated TLR3 signaling activation could account for the pathogenesis of active EBV-infectious diseases.

Figure 1

Secondary structures of EBERs. Reproduced from Rosa et al. [4]. EBER, Epstein-Barr virus-encoded RNA.

Figure 2

EBER-mediated modulation of innate immune signaling contributes to EBV-mediated pathogenesis. Reproduced from Iwakiri et al. [71]. Left, in BL cells, EBERs are recognized by RIG-I via the RNA helicase domain of RIG-I and following recognition, RIG-I associates with the adaptor IPS-1 via its CARD. IPS-1 initiates signaling leading to the activation of IRF3 and NF-κB to induce type I IFNs and inflammatory cytokine expression. EBERs induce the expression of the growth-promoting cytokine IL-10 via RIG-I-mediated IRF3 activation and might support BL development. EBERs also bind to IFN-inducible PKR and block its activity, which is required for the IFN-mediated antiviral effect; therefore, EBV might maintain a latent infection state. Right, activation of innate immunity via TLR3 signaling in response to secreted EBER. During an active EBV-infection, EBER1 is released from EBV-infected lymphocytes primarily in a complex with La. Circulating EBER induces DC maturation via TLR3 signaling and induces type I IFN and inflammatory cytokine production by activating IRF3 and NF-κB. DC activation leads to T cell activation and systemic cytokine release. Furthermore, TLR3-expressing T and NK cells including EBV-infected T or NK cells could be activated by EBER1 through TLR3, thus leading to inflammatory cytokine production. Therefore, immunopathologic diseases caused by active EBV infections including T or NK cell activaiton and hypercytokinemia, could be attributed to EBER1-induced TLR3-mediated T cell activation and cytokinemia. EBER, Epstein-Barr virus encoded RNA; EBV, Epstein-Barr virus; BL, Burkitt’s lymphoma; IPS-1, interferon-β promoter stimulator-1; CARD, caspase recruitment domain; RIG-I, retinoic acid-inducible gene I; DC, dendritic cell; IFN, interferon; NK cell, natural killer cell; IL, interleukin; TLR, Toll-like receptor; PKR, RNA-dependent protein kinase; IRF 3, interferon regulatory factor 3.