Abstract：
Maternal Zika virus (ZIKV) infection during pregnancy has been associated with severe intrauterine growth restriction (IUGR), placental damage, metabolism disturbances, and newborn neurological abnormalities. Here, we investigated the impact of maternal ZIKV infection on placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) or High (5 × 107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, and tissue was collected at GD18.5 (term). Fetal-placental growth was impaired in male fetuses, which exhibited higher placental expression of the ZIKV infective marker, eukaryotic translation initiation factor 2 (eIF2α), but lower levels of phospho-eIF2α. There were no differences in fetal-placental growth in female fetuses, which exhibited no significant alterations in placental ZIKV infective markers. Furthermore, ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentae, with no differences in amino acid transport potential. In contrast, ZIKV did not impact glucose transporters in male placentae but downregulated sodium-coupled neutral amino acid 2 (Snat2) transporter expression. We also observed sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV-infected pregnancies, showing that ZIKV can disturb placental nutrient sensing. Our findings highlight molecular alterations in the placenta caused by maternal ZIKV infection, shedding light on nutrient transport, sensing, and availability. Our results also suggest that female and male placentae employ distinct coping mechanisms in response to ZIKV-induced metabolic changes, providing insights into therapeutic approaches for congenital Zika syndrome.
摘要：
妊娠期母体寨卡病毒（ZIKV）感染与严重的宫内生长受限（IUGR）有关。胎盘损伤,新陈代谢紊乱，和新生儿神经异常。这里,我们调查了母体ZIKV感染对胎盘营养转运蛋白和营养敏感途径的影响.免疫活性(C57BL/6)小鼠在妊娠日(GD)12.5注射低(103PFU-ZIKVPE243)或高(5X107PFU-ZIKVPE243)ZIKV滴度,并在GD18.5(足月)收集组织。男性胎儿的胎儿胎盘生长受损，ZIKV感染标记物的胎盘表达更高，真核翻译起始因子2（eIF2α），但较低水平的磷酸-eIF2α。女性胎儿的胎儿胎盘生长没有差异，胎盘ZIKV感染标志物无明显改变。此外，ZIKV促进女性胎盘中1型葡萄糖转运蛋白（Slc2a1/Glut1）的表达增加，6-磷酸葡萄糖水平降低，氨基酸转运潜力没有差异。相比之下,ZIKV不影响男性胎盘中的葡萄糖转运蛋白，但下调钠偶联中性氨基酸2（Snat2）转运蛋白的表达。我们还观察到ZIKV感染的妊娠中己糖胺生物合成途径（HBP）和O-GlcNAcylation的性别依赖性差异，表明ZIKV可以干扰胎盘营养感知。我们的发现强调了由母体ZIKV感染引起的胎盘分子改变，揭示养分运输，传感,和可用性。我们的结果还表明，女性和男性胎盘采用不同的应对机制来应对ZIKV诱导的代谢变化，为先天性寨卡综合征的治疗方法提供见解。
