Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-λ signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN-λ2 reduced ZIKV infection. IFN-λ treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage dependence of ZIKV pathogenesis and IFN-λ-mediated immunity at the maternal-fetal interface.

尽管寨卡病毒（ZIKV）引起的先天性疾病在妊娠早期更频繁地发生，但其基础仍不确定。使用已建立的子宫内ZIKV传播的I型干扰素（IFN）缺陷型小鼠模型，我们发现胎盘和胎儿在妊娠早期更易受ZIKV感染。胚胎第6天（E6）的ZIKV感染导致胎盘功能不全和胎儿死亡，而中期（E9）的感染导致颅骨面积缩小，怀孕后期（E12）的感染没有引起明显的胎儿疾病。此外，我们发现缺乏III型IFN-λ信号传导的胎儿在E12感染时胎盘和胎儿中的ZIKV复制增加，并且相应地，用IFN-λ2孕鼠治疗可减少ZIKV感染。IFN-λ治疗类似地减少了人类妊娠中期胎儿和母体来源的外植体中的ZIKV感染。我们的数据建立了ZIKV发病机理和母胎界面处IFN-λ介导的免疫的妊娠期依赖性模型。