Epstein-Barr virus-infected cells release Fas ligand in exosomal fractions and induce apoptosis in recipient cells via the extrinsic pathway
Epstein-Barr virus-infected cells release Fas ligand in exosomal fractions and induce apoptosis in recipient cells via the extrinsic pathway
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DOI：
10.1099/jgv.0.000313
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发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Khan, Gulfaraz
中科院分区：
文献类型：
--
作者：
Ahmed, Waqar;Philip, Pretty S.;Khan, Gulfaraz
EB病毒（EBV;人类疱疹病毒4）是一种致癌性疱疹病毒，与几种人类恶性肿瘤的发病机制有关。最近的一些研究表明，EBV可以通过在称为外泌体的纳米囊泡中分泌病毒和细胞组分来操纵局部微环境。在这项研究中，我们研究了EBV来源的外泌体对受体细胞凋亡的影响以及参与这一过程的分子途径。来自EBV感染的细胞而不是来自未感染的细胞的外来体在许多不同的细胞类型中诱导凋亡，包括B细胞、T细胞和上皮细胞。然而，这种现象并不普遍，伯基特淋巴瘤衍生的B细胞系BJAB被发现对细胞凋亡有抗性。来自I型和III型EBV潜伏感染细胞的外来体以剂量和时间依赖性方式诱导细胞凋亡。此外，暴露于EBV外泌体的细胞在软琼脂测定中不形成集落。我们进一步表明，来自EBV感染细胞的荧光标记的外泌体被未感染细胞吸收，并通过外源性途径诱导细胞凋亡。caspase-3/7/8的抑制阻断EBV外泌体介导的细胞凋亡。此外，我们的数据表明EBV外泌体通过Fas配体（FasL）介导的外源性途径触发细胞凋亡，因为FasL存在于EBV外泌体组分中，并且抗FasL抗体可以阻断EBV外泌体介导的细胞凋亡。总之，这些数据支持EBV劫持外泌体途径以分泌可以调节其微环境的病毒和细胞组分的观点。
Epstein-Barr virus (EBV; human herpesvirus 4) is an oncogenic herpesvirus implicated in the pathogenesis of several human malignancies. A number of recent studies indicate that EBV can manipulate the local microenvironment by excreting viral and cellular components in nanovesicles called exosomes. In this study, we investigated the impact of EBV-derived exosomes on apoptosis of recipient cells and the molecular pathway involved in this process. Exosomes from EBV-infected but not from non-infected cells induced apoptosis in a number of different cell types, including B-cells, T-cells and epithelial cells. However, this phenomenon was not universal and the Burkitt's lymphoma-derived B-cell line BJAB was found to be resistant to apoptosis. Exosomes from both type I and type III EBV latently infected cells induced apoptosis in a dose- and time-dependent manner. Moreover, cells exposed to EBV exosomes did not form colonies in soft agar assays. We further show that fluorescently labelled exosomes derived from EBV-infected cells are taken up by non-infected cells and induce apoptosis via the extrinsic pathway. Inhibition of caspase-3/7/8 blocks EBV exosome-mediated apoptosis. Furthermore, our data indicate that EBV exosomes trigger apoptosis through the Fas ligand (FasL)-mediated extrinsic pathway, as FasL was present in EBV exosomal fractions and anti-FasL antibodies could block EBV exosome-mediated apoptosis. Together, these data support the notion that EBV hijacks the exosome pathway to excrete viral and cellular components that can modulate its microenvironment.