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) 会导致小头畸形并破坏神经发生。Dicer 介导的 miRNA 生物发生是胚胎大脑发育所必需的，并且已被建议在 ZIKV 感染后被破坏。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 Dicer 被 ZIKV 的衣壳特异性靶向，而不是其他黄病毒，以促进 ZIKV 感染。我们确定了失去这种相互作用并且不抑制 Dicer 活性的衣壳突变体 (H41R)。始终如一地，ZIKV-H41R 的毒性较低，并且不会抑制体外神经发生或子宫内皮质发生. 流行性 ZIKV 毒株含有衣壳突变，可增加 Dicer 结合亲和力并增强致病性。ZIKV 感染的 NSC 显示出 miRNA 产生的整体抑制，包括与神经发生相关的关键 miRNA，这在 ZIKV-H41R 感染后未观察到。这些发现共同表明，衣壳依赖性 Dicer 抑制是 ZIKV 免疫逃避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。