携带EV71病毒粒子的微泡通过内吞途径穿过血脑屏障诱导脑损伤。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Xiaoyan Tian, Bingxin Liu, Linrun Li, Meng Yuan, Qiao You, Rui Zhang, Deyan Chen, Min Cheng, Nan Zheng, Miao He, Zhiwei Wu
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引用次数: 0

摘要

肠病毒71型(EV71)是幼儿手足口病(手足口病)的主要病原。EV71感染的严重病例可能导致神经系统并发症甚至死亡,而引起神经系统并发症的机制仍然知之甚少。在本研究中,我们首次证明了微囊泡(MVs)可以携带EV71病毒粒子并介导更高的感染效率。利用体外血脑屏障(BBB)模型,我们观察到含有病毒粒子(MVsEV71)的mv比单独的EV71更能有效地穿过血脑屏障。通过体内成像,我们证实了mv穿过血脑屏障的能力。qPCR分析显示,与游离EV71处理的小鼠相比,MVsEV71处理的小鼠血液和脑样本中EV71的拷贝数更高。此外,我们的研究发现,与体内感染EV71的动物相比,感染MVsEV71的动物可引起脑出血和更严重的脑炎症浸润。此外,我们发现连接蛋白如zo1 -1 (ZO-1)和occludin的表达减少。此外,使用化学抑制剂阻断内吞途径,检测了脑细胞对mv的摄取。我们的实验表明,内化的mv通过不依赖网格蛋白的机制发生,并且一部分内化的mv进入溶酶体。此外,我们发现受损的线粒体是MVs的“货物”,这促进了MVsEV71穿过血脑屏障并诱导细胞凋亡。同时,MVsEV71穿过血脑屏障进一步诱导U251细胞线粒体损伤并激活nox4来源的ROS通路。综上所述,这些发现表明,MVs通过血脑屏障运输EV71病毒粒子,而受损的线粒体促进了这一过程,并加重了脑损伤。总的来说,这些观察结果为ev71诱导的神经源性并发症提供了新的见解,并为病毒性脑炎的治疗提供了新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Microvesicles carrying EV71 virions cross BBB through endocytic pathway to induce brain injury.

Enterovirus 71 (EV71) is a major etiologic pathogen for hand-foot-and-mouth disease (HFMD) in young children. Severe cases of EV71 infection could lead to neurological complications and even death, while the mechanism inducing neurological complications remains poorly understood. In this study, we firstly proved that microvesicles (MVs) could carry EV71 virions and mediate a higher efficiency in infection. Utilizing an in vitro blood-brain barrier (BBB) model, we observed that MVs containing virions (MVsEV71) could cross the BBB with greater efficiency compared to EV71 alone. Through in vivo imaging, we confirmed the ability of MVs to cross the BBB. qPCR assays showed a higher copy number of EV71 in both blood and brain samples in the mice treated with MVsEV71 compared to those treated with free EV71. Also, our investigation unveiled that MVsEV71 infection of animals induced cerebral hemorrhage and more severe inflammatory infiltration in the brain compared to animals infected by EV71 in vivo. Furthermore, we found a reduction in the expression of junction proteins such as zonula occludens-1 (ZO-1) and occludin. Moreover, the uptake of MVs by brain cells was examined using chemical inhibitor to block the endocytic pathway. Our experiments elucidated that the internalization of MVs occurred via a non-clathrin-dependent mechanism and a portion of the internalized MVs proceeded to enter lysosomes. In addition, we identified damaged mitochondria as the "cargo" of MVs, which facilitated MVsEV71 crossing the BBB and inducing cellular apoptosis. Meanwhile, MVsEV71 crossing the BBB further induced mitochondrial damaged and activated NOX4-derived ROS pathway in U251 cells. Taken together, these findings suggested that MVs transported EV71 virions across the BBB, while damaged mitochondria facilitated this process and aggravated the brain injury. Overall, these observations provide new insights into EV71-induced neurogenic complications and present a novel therapeutic target for the treatment of viral encephalitis.

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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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