上海交通大学医学院梁启明、美国南加州大学医学院赵振和杜兰大学Shitao Li团队合作取得新进展。他们发现寨卡病毒（ZIKV）衣壳蛋白通过抑制Dicer酶活性和miRNA生物发生来破坏皮质发生。这一研究成果在线发表在2020年8月7日的《细胞-干细胞》上。

研究人员在神经干细胞（NSCs）中绘制了ZIKV与宿主相互作用的基因组，发现ZIKV 衣壳蛋白特异地靶向Dicer以促进ZIKV感染，而Dicer不会被其他黄病毒靶向。研究人员发现衣壳蛋白H41R突变体失去了这种相互作用，并且不抑制Dicer酶活性。与此一致，ZIKV-H41R病毒毒性较低，并且不抑制体外神经发育或子宫内皮质发生。流行的包含衣壳突变的ZIKV菌株增强了与Dicer的结合亲和力从而增加致病性。ZIKV感染NSC后总体抑制miRNA的产生，包括与神经发生相关的关键miRNA，这是在ZIKV-H41R感染后未观察到的。

这些发现共同表明，衣壳蛋白依赖的Dicer酶抑制是ZIKV免疫逃逸和发病的决定因素，这也可能是ZIKV相关小头畸形的成因。

研究人员表示，ZIKV引起小头畸形并破坏神经发生。Dicer介导的miRNA生物发生是胚胎脑发育所必需的，ZIKV感染后会破坏其活性。

附：英文原文

Title: The Zika Virus Capsid Disrupts Corticogenesis by Suppressing Dicer Activity and miRNA Biogenesis

Author: Jianxiong Zeng, Shupeng Dong, Zhifei Luo, Xiaochun Xie, Bishi Fu, Ping Li, Chengrong Liu, Xing Yang, Yujie Chen, Xin Wang, Zhenshan Liu, Jing Wu, Youzhen Yan, Feng Wang, Jian-Fu Chen, Jian Zhang, Gang Long, Steven A. Goldman, Shitao Li, Zhen Zhao, Qiming Liang

Issue&Volume: 2020-08-06

Abstract: Zika virus (ZIKV) causes microcephaly and disrupts neurogenesis. Dicer-mediated miRNAbiogenesis is required for embryonic brain development and has been suggested to bedisrupted upon ZIKV infection. Here we mapped the ZIKV-host interactome in neuralstem cells (NSCs) and found that Dicer is specifically targeted by the capsid fromZIKV, but not other flaviviruses, to facilitate ZIKV infection. We identified a capsidmutant (H41R) that loses this interaction and does not suppress Dicer activity. Consistently,ZIKV-H41R is less virulent and does not inhibit neurogenesis in vitro or corticogenesis in utero. Epidemic ZIKV strains contain capsid mutations that increase Dicer binding affinityand enhance pathogenicity. ZIKV-infected NSCs show global dampening of miRNA production,including key miRNAs linked to neurogenesis, which is not observed after ZIKV-H41Rinfection. Together these findings show that capsid-dependent suppression of Diceris a major determinant of ZIKV immune evasion and pathogenesis and may underlie ZIKV-relatedmicrocephaly.

DOI: 10.1016/j.stem.2020.07.012

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30350-7