{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:28:12Z","timestamp":1792024092189,"version":"4.4.0"},"reference-count":28,"publisher":"Rockefeller University Press","issue":"10","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,9,28]]},"abstract":"<jats:p>Epstein-Barr virus\u2013encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)\u2013like 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.<\/jats:p>","DOI":"10.1084\/jem.20081761","type":"journal-article","created":{"date-parts":[[2009,8,31]],"date-time":"2009-08-31T21:43:22Z","timestamp":1251755002000},"page":"2091-2099","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":287,"title":["Epstein-Barr virus (EBV)\u2013encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3"],"prefix":"10.1084","volume":"206","author":[{"given":"Dai","family":"Iwakiri","sequence":"first","affiliation":[{"name":"Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinal","family":"Samanta","sequence":"additional","affiliation":[{"name":"Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misako","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ebihara","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Seya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shosuke","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Microbiology 3 and 4"},{"name":"Department of Pediatrics, Kochi Medical School, Kochi University, Nangoku 783-8505, Japan 3 and 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikiya","family":"Fujieda","sequence":"additional","affiliation":[{"name":"Department of Microbiology 3 and 4"},{"name":"Department of Pediatrics, Kochi Medical School, Kochi University, Nangoku 783-8505, Japan 3 and 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisei","family":"Kawa","sequence":"additional","affiliation":[{"name":"Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi 594-1101, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenzo","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,8,31]]},"reference":[{"key":"2023072917290397600_bib1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nri1391","article-title":"Toll-like receptor signalling","volume":"4","author":"Akira","year":"2004","journal-title":"Nat. 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