Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids
Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids
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DOI：
10.1016/j.stem.2016.12.005
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发表时间：
2017-03-02
期刊：
影响因子：
23.9
通讯作者：
Gopalakrishnan, Jay
中科院分区：
文献类型：
--
作者：
Gabriel, Elke;Ramani, Anand;Gopalakrishnan, Jay
最近的寨卡病毒流行与新生儿小头症有关。尽管寨卡病毒与神经发育缺陷之间的联系已被广泛认识，但其潜在机制尚不清楚。本研究表明，最近分离的两种ZIKV毒株，一种来自受感染胎儿脑的美国毒株（FB-GWUH-2016）和一种密切相关的亚洲毒株（H/PF/2013），可有效感染人类ipsc衍生的脑类器官。这两种菌株都容易靶向和复制增殖心室区（VZ）顶端祖细胞。主要的表型效应是与中心体扰动相关的神经祖细胞的过早分化，甚至在感染的早期阶段，导致祖细胞耗竭、VZ破坏、神经发生受损和皮层变薄。感染模式和细胞结果与广泛传代的寨卡病毒MR766不同。我们在感染这些最近分离的病毒株后看到的结构变化与寨卡病毒相关的小头畸形非常相似。
The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.