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.

Detection of Epstein-Barr virus genome and latent infection gene expression in normal epithelia, epithelial dysplasia, and squamous cell carcinoma of the oral cavity

“…As EBER is detected in healthy adults with a history of EBV infection, there is a need for caution with evaluation. EBER localization sites in EBVinfected cells are primarily the nucleus but also the cytoplasm [65]. Therefore, there is a need to evaluate both the nucleus and the cytoplasm.…”

Fresh Insights into Disease Etiology and the Role of Microbial Pathogens

“…Under specific viral programs, EBV is also recognized by other TLRs, such as TLR7 and its downstream signaling mediators, IRF5 and IRF7 in B-lymphocytes [47,48]. Moreover, the Epstein-Barr-virus-encoded small RNAs (EBERs) are also implicated as mediators of innate immune activation since they can interact with both the RIG-I and TLR3 sensors of adjacent cells when released by infected cells [49,50]. Together, these results suggest that activation of the innate immune response by EBV is dependent on the viral programs carried in the infected cells.…”

Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease

“…However, it proves difficult to demonstrate the direct involvement of EBV in these diseases, as was recently discussed for EBV and MS (Lassmann et al 2011). General consensus seems exist for a role of EBV as inflammatory trigger, possibly through the release of EBER molecules into the circulation, providing general innate and adaptive activation signals (Iwakiri 2014) and EBNA1-DNA complexes as a rich source of antigen sequences that may induce cross-reactive antibodies, depending on the host MHC-II background (Yadav et al 2011). The release of complex and structured multi-epitope EBNA1-DNA complexes presented on APC during the cytokine-rich convalescent phase of mononucleosis together with innate signalling triggered by released EBER-protein/exosome complexes may trigger autoantibody formation by crossing the tolerance threshold and extending the restricted repertoire to include autoreactive clones, a phenomenon called epitope spreading (Füst 2013;Cornaby et al 2014).…”