Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States.
Duke Human Vaccine Institute, Duke University, Durham, United States.
Elife. 2022 Aug 17;11:e79794. doi: 10.7554/eLife.79794.
Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed matched trophoblast (TO) and decidua organoids (DO) from human placentas to define the relative contributions of these cells to antiviral defenses at the maternal-fetal interface. We demonstrate that TO and DO basally secrete distinct immunomodulatory factors, including the constitutive release of the antiviral type III interferon IFN-λ2 from TOs, and differentially respond to viral infections through the induction of organoid-specific factors. Finally, we define the differential susceptibility and innate immune signaling of TO and DO to human cytomegalovirus (HCMV) and develop a co-culture model of TO and DO which showed that trophoblast-derived factors protect decidual cells from HCMV infection. Our findings establish matched TO and DO as ex vivo models to study vertically transmitted infections and highlight differences in innate immune signaling by fetal-derived trophoblasts and the maternal decidua.
在母体-胎儿界面处的感染可能直接损害胎儿，并引发不良妊娠结局的并发症。胎儿来源的胎盘滋养层和母体蜕膜中的固有免疫信号必须在这个关键界面提供抗微生物防御，而不损害其完整性。在这里，我们从人胎盘开发了匹配的滋养层 (TO) 和蜕膜类器官 (DO)，以定义这些细胞对母体-胎儿界面抗病毒防御的相对贡献。我们证明，TO 和 DO 基础分泌不同的免疫调节因子，包括 TO 中抗病毒的 III 型干扰素 IFN-λ2 的组成性释放，并且通过诱导器官特异性因子来对病毒感染产生不同的反应。最后，我们确定了 TO 和 DO 对人巨细胞病毒 (HCMV) 的差异敏感性和固有免疫信号，并开发了 TO 和 DO 的共培养模型，表明滋养层衍生的因子可保护蜕膜细胞免受 HCMV 感染。我们的研究结果确立了匹配的 TO 和 DO 作为研究垂直传播感染的体外模型，并强调了胎儿来源的滋养层和母体蜕膜中固有免疫信号的差异。
