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¹ Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
² Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
³ Department of Microbiology and ⁴ Department of Pediatrics, Kochi Medical School, Kochi University, Nangoku 783-8505, Japan
⁵ Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi 594-1101, Japan

CORRESPONDENCE Kenzo Takada: kentaka{at}igm.hokudai.ac.jp

Epstein-Barr virus–encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)–like molecules, and exists abundantly in EBV-infected cells. Here, we report that EBER induces signaling from the Toll-like receptor 3 (TLR3), which is a sensor of viral double-stranded RNA (dsRNA) and induces type I IFN and proinflammatory cytokines. A substantial amount of EBER, which was sufficient to induce signaling from TLR3, was released from EBV-infected cells, and the majority of the released EBER existed as a complex with a cellular EBER-binding protein La, suggesting that EBER was released from the cells by active secretion of La. Sera from patients with infectious mononucleosis (IM), chronic active EBV infection (CAEBV), and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), whose general symptoms are caused by proinflammatory cytokines contained EBER, and addition of RNA purified from the sera into culture medium induced signaling from TLR3 in EBV-transformed lymphocytes and peripheral mononuclear cells. Furthermore, DCs treated with EBER showed mature phenotype and antigen presentation capacity. These findings suggest that EBER, which is released from EBV-infected cells, is responsible for immune activation by EBV, inducing type I IFN and proinflammatory cytokines. EBER-induced activation of innate immunity would account for immunopathologic diseases caused by active EBV infection.

Abbreviations used: CAEBV, chronic active EBV infection; dsRNA, double-stranded RNA; EBER, EBV-encoded small RNA; EBV-HLH, EBV-associated hemophagocytic lymphohistiocytosis; IM, infectious mononucleosis; IRF, IFN-regulatory factor; La, lupus erythematosis-associated antigen; LCL, lymphoblastoid cell line; PKR, RNA-activated protein kinase; RIG-I, retinoic acid–inducible gene-I; TLR, Toll-like receptor.

© 2009 Iwakiri et al.
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