Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection.
Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection.
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DOI：
10.1371/journal.ppat.1006611
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发表时间：
2017-09
期刊：
影响因子：
6.7
通讯作者：
Wu Z
中科院分区：
文献类型：
--
作者：
Fu Y;Zhang L;Zhang F;Tang T;Zhou Q;Feng C;Jin Y;Wu Z
外泌体可以在细胞间传递遗传物质。它们在病毒感染中的作用开始得到重视。研究表明，病毒感染细胞释放的外泌体含有多种病毒和宿主细胞因子，这些因子能够调节受体的细胞反应并导致受体宿主的生产性感染。在这里，我们发现EV71感染导致外泌体分泌上调，病毒基因组RNA和miR-146a被不同地包装到外泌体中。我们提供的证据表明，miR-146a在外泌体中优先富集，而病毒RNA不在感染细胞中富集。此外，这些外泌体含有与miR-146a、Ago2和GW182复合物的复制能力强的EV71 RNA，可以介导不依赖于病毒特异性受体的EV71传播。外泌体病毒RNA可以转移到新的靶细胞中进行复制，而外泌体miR-146a抑制了靶细胞中I型干扰素的反应，从而促进了病毒的复制。此外，我们发现ifn刺激基因因子（ISGs） BST-2/tetherin参与了ev71诱导的外泌体分泌上调。重要的是，体内研究表明，与游离病毒颗粒相比，外泌体病毒RNA表现出不同的组织积累。总之，我们的研究结果提供了证据，证明EV71感染细胞分泌的外泌体选择性地包装了高水平的miR-146a，该miR-146a可以通过抑制I型干扰素反应功能性地转移到EV71外泌体RNA并促进其在受体细胞中复制。外泌体是小的膜包裹的囊泡，分泌到细胞外环境中。在外泌体中发现了各种蛋白质和RNA分子，其含量反映了宿主细胞的生理或病理状态。研究表明，病毒感染细胞释放的外泌体含有多种病毒和宿主细胞因子，这些因子能够调节受体的细胞反应并导致受体宿主的生产性感染。在这里，我们发现肠病毒71 (EV71)，一种无包膜的单链阳性RNA病毒，属于小核糖核酸科，是手足口病（HFMD）的主要病原体，可以刺激外泌体分泌和病毒基因组RNA和miR-146a的差异包装到外泌体中。外泌体病毒RNA可以转移到新的靶细胞中进行复制，而外泌体miR-146a抑制了靶细胞中I型干扰素的反应，从而促进了病毒的复制。重要的是，体内研究表明，与游离病毒颗粒相比，外泌体病毒RNA表现出不同的组织积累。我们推测miRNA-146a优先包装入外泌体是病毒在感染时抑制宿主先天免疫的一种策略，外泌体EV 71 RNA可能在感染中起重要的致病作用。
Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR-146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs), BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71-infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response. Exosomes are small membrane-encapsulated vesicles that secrete into the extracellular environment. Various proteins and RNA molecules have been identified in exosomes whose content reflects the physiological or pathological state of the host cells. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular responses and result in productive infection of the recipient host. Here, we showed that Enterovirus 71 (EV71), a non-enveloped, single-strand positive sense RNA virus that belongs to the family Picornaviridae and is a major etiologic agent of hand-foot and-mouth disease (HFMD), could stimulate exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. We postulate that the preferential packaging of miRNA-146a into exosome is a viral strategy of suppressing host innate immunity upon infection and the exosomal EV 71 RNA may play an important pathogenic role in the infection.
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DOI：
10.3390/v7062770
发表时间：
2015-06-19
期刊：
Viruses
影响因子：
--
作者：
Chahar HS;Bao X;Casola A
通讯作者：
Casola A
影响因子：
64.8
作者：
Feng Z;Hensley L;McKnight KL;Hu F;Madden V;Ping L;Jeong SH;Walker C;Lanford RE;Lemon SM
通讯作者：
Lemon SM
影响因子：
7.7
作者：
Edgar, James R.;Manna, Paul T.;Robinson, Margaret S.
通讯作者：
Robinson, Margaret S.
影响因子：
5.4
作者：
Hurwitz, Stephanie N.;Nkosi, Dingani;Meckes, David G., Jr.
通讯作者：
Meckes, David G., Jr.
影响因子：
16.6
作者：
Ho, Bing-Ching;Yu, I-Shing;Yu, Sung-Liang
通讯作者：
Yu, Sung-Liang