Secreted Oral Epithelial Cell Membrane Vesicles Induce Epstein-Barr Virus Reactivation in Latently Infected B Cells
Secreted Oral Epithelial Cell Membrane Vesicles Induce Epstein-Barr Virus Reactivation in Latently Infected B Cells
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DOI：
10.1128/jvi.02830-15
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发表时间：
2016-04-01
影响因子：
5.4
通讯作者：
Flemington, Erik K.
中科院分区：
文献类型：
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作者：
Lin, Zhen;Swan, Kenneth;Flemington, Erik K.
在口腔上皮中，EB病毒（EBV）的外周储存从浸润性B细胞传播到上皮细胞。一旦病毒被传播到上皮细胞，这种细胞类型对裂解复制的高度容许性允许病毒扩增并交换到其他宿主。由于EBV从B细胞向上皮细胞的初始转移需要B细胞转变为诱导病毒再活化的状态，我们假设可能存在上皮特异性信号，其允许浸润的B细胞感知合适的环境以启动再活化并开始该交换过程。我们先前发现上皮特异性miR-200家族的microRNA促进EBV裂解性复制。在这里，我们发现在口腔和扁桃体上皮和唾液中有高水平的miR-200家族成员。对培养的口腔上皮细胞（OKF 6）的分析表明，它们主动分泌富含miR-200家族成员的膜囊泡（外来体）。EBV阳性B细胞与OKF 6细胞共培养诱导病毒再活化。此外，用OKF 6细胞衍生的膜囊泡处理EBV阳性B细胞促进再活化。使用不天然表达miR-200家族成员的细胞系统，我们发现miR-200家族成员的强制表达产生能够在EBV阳性B细胞中诱导裂解级联的膜囊泡。我们建议，口腔和扁桃体上皮细胞分泌的膜囊泡可能作为一个组织特异性的环境线索，启动重新激活的B细胞，促进转移的病毒从外周B细胞商店的口腔上皮细胞，以促进病毒扩增和交换到其他主机。
In the oral epithelium, peripheral stores of Epstein-Barr virus (EBV) are transmitted from infiltrating B cells to epithelial cells. Once the virus is transmitted to epithelial cells, the highly permissive nature of this cell type for lytic replication allows virus amplification and exchange to other hosts. Since the initial transfer of EBV from B cells to epithelial cells requires transitioning of the B-cell to a state that induces virus reactivation, we hypothesized that there might be epithelium-specific signals that allow the infiltrating B cells to sense the appropriate environment to initiate reactivation and begin this exchange process. We previously found that the epithelium-specific miR-200 family of microRNAs promotes EBV lytic replication. Here we show that there are high levels of miR-200 family members in oral and tonsillar epithelia and in saliva. Analysis of cultured oral epithelial cells (OKF6) showed that they actively secrete membrane vesicles (exosomes) that are enriched with miR-200 family members. Coculturing of EBV-positive B cells with OKF6 cells induced viral reactivation. Further, treatment of EBV-positive B cells with OKF6 cell-derived membrane vesicles promoted reactivation. Using a cell system that does not naturally express miR-200 family members, we found that enforced expression of a miR-200 family member produced membrane vesicles that were able to induce the lytic cascade in EBV-positive B cells. We propose that membrane vesicles secreted by oral and tonsillar epithelial cells may serve as a tissue-specific environmental cue that initiates reactivation in B cells, promoting the transfer of virus from peripheral B-cell stores to the oral epithelium to facilitate virus amplification and exchange to other hosts.