{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:36:56Z","timestamp":1791196616836,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2012,9,1]],"date-time":"2012-09-01T00:00:00Z","timestamp":1346457600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Epstein-Barr virus (EBV), a human gamma herpesvirus, establishes a life-long latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence indicate that the efficiency of EBV infection in epithelial cells is accelerated up to 10\n            <jats:sup>4<\/jats:sup>\n            -fold by coculturing with EBV-infected Burkitt's lymphoma (BL) cells compared to infection with cell-free virions, indicating that EBV infection into epithelial cells is mainly mediated via cell-to-cell contact. However, the molecular mechanisms involved in this pathway are poorly understood. Here, we establish a novel assay to assess cell-to-cell contact-mediated EBV transmission by coculturing an EBV-infected BL cell line with an EBV-negative epithelial cell line under stimulation for lytic cycle induction. By using this assay, we confirmed that EBV was transmitted from BL cells to epithelial cells via cell-to-cell contact but not via cell-to-cell fusion. The inhibitor treatments of extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-\u03baB pathways blocked EBV transmission in addition to lytic induction. The blockage of the phosphoinositide 3-kinase (PI3K) pathway impaired EBV transmission coupled with the inhibition of lytic induction. Knockdown of the RelA\/p65 subunit of NF-\u03baB reduced viral transmission. Moreover, these signaling pathways were activated in cocultured BL cells and in epithelial cells. Finally, we observed that viral replication was induced in cocultured BL cells. Taken together, our data suggest that cell-to-cell contact induces multiple cell signaling pathways in BL cells and epithelial cells, contributing to the induction of the viral lytic cycle in BL cells and the enhancement of viral transmission to epithelial cells.\n          <\/jats:p>","DOI":"10.1128\/jvi.00712-12","type":"journal-article","created":{"date-parts":[[2012,6,21]],"date-time":"2012-06-21T13:33:35Z","timestamp":1340285615000},"page":"9285-9296","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Roles of Cell Signaling Pathways in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission"],"prefix":"10.1128","volume":"86","author":[{"given":"Asuka","family":"Nanbo","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruna","family":"Terada","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Kachi","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenzo","family":"Takada","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02471470"},{"key":"e_1_3_2_3_2","first-page":"1703","article-title":"Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach","volume":"43","author":"Barranco SC","year":"1983","unstructured":"BarrancoSC. 1983. Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach. 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Autocrine growth of Epstein-Barr virus-positive gastric carcinoma cells mediated by an Epstein-Barr virus-encoded small RNA. Cancer Res. 63:7062\u20137067.","journal-title":"Cancer Res."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2004.00209.x"},{"key":"e_1_3_2_19_2","volume-title":"Human herpesviruses: biology, therapy, and immunoprophylaxis, chapter 25.","author":"Kenney SC","year":"2007","unstructured":"KenneySC. 2007. Reactivation and lytic replication of EBV. In ArvinA (ed), Human herpesviruses: biology, therapy, and immunoprophylaxis, chapter 25. Cambridge University Press, Cambridge, United Kingdom."},{"key":"e_1_3_2_20_2","first-page":"2511","volume-title":"Fields virology","author":"Kieff E","year":"2001","unstructured":"KieffE RickinsonAB. 2001. Epstein-Barr virus and its replication, p 2511\u20132573. In KnipeDM (ed), Fields virology, 4th ed. 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