Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice
Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice
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寨卡病毒破坏神经祖细胞发育并导致小鼠小头畸形
DOI：
10.1016/j.stem.2016.04.017
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发表时间：
2016-07-07
期刊：
影响因子：
23.9
通讯作者：
Xu, Zhiheng
中科院分区：
文献类型：
--
作者：
Li, Cui;Xu, Dan;Xu, Zhiheng
寨卡病毒（ZIKV）感染和小头畸形症之间的联系引起了全球的紧急警报。历史上的非洲ZIKV MR766最近被证明感染培养的人类神经前体细胞（NPC），但与当代ZIKV菌株不同，它不被认为会导致小头畸形。在这里，我们研究了亚洲ZIKV毒株SZ 01是否可以在体内感染NPC并影响脑发育。我们发现SZ 01通过直接靶向不同的神经元谱系在胚胎小鼠脑中有效复制。ZIKV感染导致细胞周期停滞、细胞凋亡和NPC分化的抑制，导致皮质变薄和小头畸形。对感染大脑的全球基因表达分析揭示了候选黄病毒进入受体的上调以及与免疫反应、细胞凋亡和小头畸形相关的基因的失调。我们的模型为寨卡病毒感染和小头畸形之间的直接联系提供了证据，有可能进一步探索大脑发育过程中ZIKV相关病理效应的潜在机制和管理。
The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcephaly, with potential for further exploration of the underlying mechanisms and management of ZIKV-related pathological effects during brain development.