Role of EBERs in the pathogenesis of EBV infection

Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are noncoding RNAs that are expressed abundantly in latently EBV-infected cells. Previous studies demonstrated that EBERs (EBER1 and EBER2) play significant roles in various EBV-infected cancer cells. EBERs are responsible for malignant phenotypes of Burkitt's lymphoma (BL) cells including resistance to apoptosis. In addition, EBERs induce the expression of interleukin (IL)-10 in BL cells, insulin-like growth factor (IGF)-1 in gastric carcinoma and nasopharyngeal carcinoma cells, IL-9 in T cells that act as an autocrine growth factor. It was also reported that EBERs play critical roles in the B cell growth transformation including IL-6 induction by EBER2. EBERs have been discovered to interact with cellular proteins that play a key role in antiviral innate immunity. They bind the protein kinase RNA-dependent (PKR) and inhibit its activation, leading to resistance to PKR-mediated apoptosis. Recently, it was demonstrated that EBERs bind RIG-I and activate its downstream signaling, which induces expression of type-I interferon (IFN)s. Furthermore, EBERs induce IL-10 through IRF3 but not NF-kappaB activation in BL cells, suggesting that modulation of innate immune signaling by EBERs contribute to EBV-mediated oncogenesis. Most recently, it was reported that EBERs are secreted from EBV-infected cells and are recognized by toll-like receptor (TLR)3, leading to induction of type-I IFNs and inflammatory cytokines, and subsequent immune activation. Furthermore, EBER1 could be detected in the sera of patients with active EBV infectious diseases, suggesting that activation of TLR3 signaling by EBER1 would be account for the pathogenesis of active EBV infectious diseases.