title: Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3.
abstract: 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.
authors.affiliation: Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Iwakiri
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Mrinal
authors.initials: M
authors.lastname: Samanta
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Ebihara
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Shosuke
authors.initials: S
authors.lastname: Imai
authors.forename: Mikiya
authors.initials: M
authors.lastname: Fujieda
authors.forename: Keisei
authors.initials: K
authors.lastname: Kawa
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takada
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis; D012367:RNA, Viral / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D016207:Cytokines; C099537:Epstein-Barr virus encoded RNA 1; C106732:Epstein-Barr virus encoded RNA 2; D012367:RNA, Viral; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta