Key Points ZIKV permissiveness of decidual cells is gestational age dependent. ZIKV-infected DC supernatants enhance ZIKV infection of trophoblasts. Tizoxanide inhibits ZIKV infection of both decidual and trophoblast cells. Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.

中文翻译：

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寨卡病毒感染的蜕膜细胞引发与孕龄相关的先天免疫反应并夸大滋养细胞寨卡病毒的容许性：垂直传播的意义

关键点 ZIKV 对蜕膜细胞的允许性取决于孕龄。ZIKV 感染的 DC 上清液增强了 ZIKV 对滋养细胞的感染。Tizoxanide 抑制蜕膜和滋养层细胞的 ZIKV 感染。寨卡病毒 (ZIKV) 的垂直传播会导致严重的胎儿缺陷，但确切的致病机制尚不清楚。我们发现，与滋养层细胞相比，人类足月蜕膜基质细胞中病毒附着因子 AXL、GAS6 和 PROS1 的表达高出 10,480 倍，ZIKV 感染性/传播增加了 3880 倍。此外，在人类妊娠早期与足月蜕膜细胞相比，病毒附着因子和 ZIKV 的水平显着增加，而先天免疫反应基因的表达显着降低。与直接感染的细胞滋养层相比，ZIKV 感染的蜕膜细胞上清液使细胞滋养层的感染增加了 252 倍。Tizoxanide 治疗有效地抑制了母体和胎儿细胞中的寨卡病毒感染。我们得出结论，ZIKV 允许性以及人类蜕膜细胞的先天免疫反应性依赖于孕龄，并且蜕膜细胞会增强原代人类细胞滋养层培养物的 ZIKV 感染，否则这些细胞对 ZIKV 具有抗性。人类蜕膜细胞可能充当 ZIKV 妊娠期依赖性胎盘传播的储存库，这是在妊娠早期与晚期妊娠中观察到的寨卡病毒感染易感性更高和更严重的胎儿后遗症的原因。此外，替唑尼特是预防围产期寨卡病毒传播以及冠状病毒等其他 RNA 病毒的有前途的药物。