Protection of ZIKV infection-induced neuropathy by abrogation of acute antiviral response in human neural progenitors
Protection of ZIKV infection-induced neuropathy by abrogation of acute antiviral response in human neural progenitors
复制标题
通过消除人类神经祖细胞的急性抗病毒反应来保护 ZIKV 感染引起的神经病变
DOI：
10.1038/s41418-019-0324-7
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发表时间：
2019-12-01
影响因子：
12.4
通讯作者：
Zhang, Xiaoqing
中科院分区：
文献类型：
--
作者：
Liu, Ling;Chen, Zhenyu;Zhang, Xiaoqing
寨卡病毒（ZIKV）感染如何导致人类新生儿严重小头畸形在很大程度上仍然未知。我们检查了亚洲谱系ZIKV，SZ 01，其类似地感染并在来自前脑背侧、前脑腹侧以及源自人多能干细胞的后脑和脊髓脑类器官的人神经祖细胞（NPC）中表现出相当的生长停滞和凋亡病理变化。转录组分析显示ZIKV感染后所有区域NPC中常见的过度活化的抗病毒应答。ZIKV感染直接激活了人NPC中IFN刺激基因（ISG）的一个亚组，其依赖于IRF 3和NF-κB的存在，而不是IFN的产生和分泌，突出了ZIKV感染引起的神经病变的IFN非依赖性急性抗病毒途径的关键作用。因此，我们的研究结果表明，过度活化的抗病毒应答在人NPC中是有害的而不是保护性的，并且IFN非依赖性急性抗病毒途径可以作为改善ZIKV感染触发的神经病变的潜在靶标。
It remains largely unknown how Zika virus (ZIKV) infection causes severe microcephaly in human newborns. We examined an Asian lineage ZIKV, SZ01, which similarly infected and demonstrated comparable growth arrest and apoptotic pathological changes in human neuroprogenitors (NPCs) from forebrain dorsal, forebrain ventral as well as hindbrain and spinal cord brain organoids derived from human pluripotent stem cells. Transcriptome profiling showed common overactivated antiviral response in all regional NPCs upon ZIKV infection. ZIKV infection directly activated a subset of IFN-stimulated genes (ISGs) in human NPCs, which depended on the presence of IRF3 and NF-κB rather than IFN production and secretion, highlighting a key role of IFN-independent acute antiviral pathway underlying ZIKV infection-caused neuropathy. Our findings therefore reveal that overactivated antiviral response is detrimental rather than protective in human NPCs, and the IFN-independent acute antiviral pathway may serve as a potential target to ameliorate ZIKV infection-triggered neuropathy.