Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Research Center of Translational Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Cell Stem Cell. 2020 Oct 1;27(4):618-632.e9. doi: 10.1016/j.stem.2020.07.012. Epub 2020 Aug 6.
Zika virus (ZIKV) causes microcephaly and disrupts neurogenesis. Dicer-mediated miRNA biogenesis is required for embryonic brain development and has been suggested to be disrupted upon ZIKV infection. Here we mapped the ZIKV-host interactome in neural stem cells (NSCs) and found that Dicer is specifically targeted by the capsid from ZIKV, but not other flaviviruses, to facilitate ZIKV infection. We identified a capsid mutant (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 affinity and enhance pathogenicity. ZIKV-infected NSCs show global dampening of miRNA production, including key miRNAs linked to neurogenesis, which is not observed after ZIKV-H41R infection. Together these findings show that capsid-dependent suppression of Dicer is a major determinant of ZIKV immune evasion and pathogenesis and may underlie ZIKV-related microcephaly.
寨卡病毒(ZIKV)可导致小头畸形并破坏神经发生。Dicer 介导的 miRNA 生物发生对于胚胎大脑发育是必需的,并且已经表明在 ZIKV 感染时会被破坏。在这里,我们绘制了神经干细胞(NSC)中的 ZIKV-宿主相互作用组,发现 ZIKV 的衣壳蛋白特异性靶向 Dicer,而不是其他黄病毒,从而促进 ZIKV 感染。我们鉴定出一种衣壳突变体(H41R),该突变体失去了这种相互作用,并且不抑制 Dicer 活性。一致地,ZIKV-H41R 的毒力降低,并且不会抑制体外的神经发生或体内的皮质发生。流行的 ZIKV 株包含增加 Dicer 结合亲和力并增强致病性的衣壳突变。感染 ZIKV 的 NSCs 显示 miRNA 产生的全局减弱,包括与神经发生相关的关键 miRNA,而在 ZIKV-H41R 感染后则没有观察到。这些发现表明,衣壳依赖性的 Dicer 抑制是 ZIKV 免疫逃逸和发病机制的主要决定因素,并且可能是 ZIKV 相关小头畸形的基础。