Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, South Korea.
Front Immunol. 2019 Apr 24;10:876. doi: 10.3389/fimmu.2019.00876. eCollection 2019.
Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, which is the most common cancer in acquired immune deficiency syndrome patients. KSHV contains a variety of immunoregulatory proteins. There have been many studies on the modulation of antiviral response by these immunoregulatory proteins of KSHV. However, the antiviral effects of extracellular vesicles (EVs) during KSHV infection have not been investigated to our best knowledge. In this study, we showed that KSHV-infected cells induce interferon-stimulated genes (ISGs) response but not type I interferon in uninfected bystander cells using EVs. mRNA microarray analysis showed that ISGs and IRF-activating genes were prominently activated in EVs from KSHV-infected cells (KSHV EVs)-treated human endothelial cells, which were validated by RT-qPCR and western blot analysis. We also found that this response was not associated with cell death or apoptosis by virus infection. Mechanistically, the cGAS-STING pathway was linked with these KSHV EVs-mediated ISGs expressions, and mitochondrial DNA on the surface of KSHV EVs was one of the causative factors. Besides, KSHV EVs-treated cells showed lower infectivity for KSHV and viral replication activity than mock EVs-treated cells. Our results indicate that EVs from KSHV-infected cells could be an initiating factor for the innate immune response against viral infection, which may be critical to understanding the microenvironment of virus-infected cells.
卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤的病原体，卡波西肉瘤是获得性免疫缺陷综合征患者中最常见的癌症。KSHV 包含多种免疫调节蛋白。已经有许多关于这些 KSHV 免疫调节蛋白对抗病毒反应的调节作用的研究。然而，据我们所知，在 KSHV 感染期间，细胞外囊泡（EVs）的抗病毒作用尚未得到研究。在这项研究中，我们使用 EVs 表明，被感染的细胞诱导干扰素刺激基因（ISGs）反应，但未诱导未感染旁观者细胞中的 I 型干扰素。mRNA 微阵列分析显示，在 KSHV 感染细胞（KSHV EVs）处理的人内皮细胞中，ISGs 和 IRF 激活基因明显被激活，这通过 RT-qPCR 和 Western blot 分析得到验证。我们还发现，这种反应与病毒感染引起的细胞死亡或凋亡无关。从机制上讲，cGAS-STING 途径与这些 KSHV EVs 介导的 ISGs 表达有关，而 KSHV EVs 表面的线粒体 DNA 是其中一个致病因素。此外，与对照 EVs 处理的细胞相比，KSHV EVs 处理的细胞对 KSHV 的感染性和病毒复制活性较低。我们的结果表明，来自 KSHV 感染细胞的 EVs 可能是针对病毒感染的固有免疫反应的起始因素，这对于理解病毒感染细胞的微环境可能至关重要。
