Key Points dsRNA induces an intrauterine antiviral response in early pregnancy. The antiviral response reduces imprinted gene expression and fetal–placental size. Type I IFNs inhibit trophoblast stem cell developmental potential. Visual Abstract Many viruses are detrimental to pregnancy and negatively affect fetal growth and development. What is not well understood is how virus-induced inflammation impacts fetal–placental growth and developmental trajectories, particularly when inflammation occurs in early pregnancy during nascent placental and embryo development. To address this issue, we simulated a systemic virus exposure in early pregnant rats (gestational day 8.5) by administering the viral dsRNA mimic polyinosinic:polycytidylic acid (PolyI:C). Maternal exposure to PolyI:C induced a potent antiviral response and hypoxia in the early pregnant uterus, containing the primordial placenta and embryo. Maternal PolyI:C exposure was associated with decreased expression of the maternally imprinted genes Mest, Sfrp2, and Dlk1, which encode proteins critical for placental growth. Exposure of pregnant dams to PolyI:C during early pregnancy reduced fetal growth trajectories throughout gestation, concomitant with smaller placentas, and altered placental structure at midgestation. No detectable changes in placental hemodynamics were observed, as determined by ultrasound biomicroscopy. An antiviral response was not evident in rat trophoblast stem (TS) cells following exposure to PolyI:C, or to certain PolyI:C-induced cytokines including IL-6. However, TS cells expressed high levels of type I IFNR subunits (Ifnar1 and Ifnar2) and responded to IFN-⍺ by increasing expression of IFN-stimulated genes and decreasing expression of genes associated with the TS stem state, including Mest. IFN-⍺ also impaired the differentiation capacity of TS cells. These results suggest that an antiviral inflammatory response in the conceptus during early pregnancy impacts TS cell developmental potential and causes latent placental development and reduced fetal growth.

中文翻译：

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早孕期间的抗病毒炎症可降低胎盘和胎儿的生长轨迹

关键点 dsRNA 在妊娠早期诱导宫内抗病毒反应。抗病毒反应减少了印迹基因的表达和胎儿-胎盘的大小。I 型干扰素抑制滋养层干细胞发育潜能。视觉摘要 许多病毒对怀孕有害，并对胎儿的生长发育产生负面影响。尚不清楚的是病毒诱导的炎症如何影响胎儿 - 胎盘的生长和发育轨迹，特别是在新生胎盘和胚胎发育期间的妊娠早期发生炎症时。为了解决这个问题，我们通过施用病毒 dsRNA 模拟多肌苷：多胞苷酸（PolyI：C）模拟了早期怀孕大鼠（妊娠第 8.5 天）的全身病毒暴露。母体暴露于 PolyI：C 在包含原始胎盘和胚胎的早期妊娠子宫中诱导有效的抗病毒反应和缺氧。母体 PolyI:C 暴露与母体印记基因 Mest、Sfrp2 和 Dlk1 的表达降低有关，这些基因编码对胎盘生长至关重要的蛋白质。妊娠早期母鼠暴露于 PolyI:C 会降低整个妊娠期间胎儿的生长轨迹，伴随着较小的胎盘，并在妊娠中期改变胎盘结构。超声生物显微镜确定未观察到胎盘血流动力学的可检测变化。暴露于 PolyI:C 或某些 PolyI:C 诱导的细胞因子（包括 IL-6）后，大鼠滋养层干 (TS) 细胞的抗病毒反应不明显。然而，TS 细胞表达高水平的 I 型 IFNR 亚基（Ifnar1 和 Ifnar2），并通过增加 IFN 刺激基因的表达和降低与 TS 干状态相关的基因（包括 Mest）的表达来响应 IFN-⍺。IFN-⍺也损害了TS细胞的分化能力。这些结果表明，妊娠早期胎体中的抗病毒炎症反应会影响 TS 细胞的发育潜力，并导致潜在的胎盘发育和胎儿生长减缓。