先天性巨细胞病毒感染人类胎盘的空间转录组学分析：广泛的抗病毒反应伴随滋养层与血管程序的同步抑制

文献信息

中文摘要

背景： 先天性巨细胞病毒（CMV）是最常见的先天性感染，也是儿童听力损失和神经发育障碍的主要感染性病因。胎盘对感染反应的细胞组织学特征尚未完全明确。方法：我们对两份CMV感染和两份未感染的晚孕期胎盘福尔马林固定组织应用Visium CytAssist空间转录组学，并通过基于参考的标签转移注释主要母源和胎儿细胞群。结果：在16,074个空间斑点中，唯一显著的组成变化是CMV感染胎盘中T细胞斑点增加和富集合体滋养层的斑点减少；其余细胞群显示相似变化但未达显著性。在各细胞类型内比较CMV感染与未感染样本的差异表达，识别出两个相反的程序。感染胎盘显示广泛的干扰素刺激基因特征，伴随CXCR3配体趋化因子、抗原加工机制、主要组织相容性复合体I类反式激活因子NLRC5、经典途径补体成分以及淋巴细胞和浆细胞标志物的诱导，在内皮、基质和合体滋养层簇中最明显，在绒毛外滋养层中最小。同时，感染胎盘显示滋养层分化和合体化基因下调，包括PAPPA2、妊娠特异性糖蛋白、CGA和GCM1，以及血管和止血基因下调，包括FLT1、VEGFA、PECAM1和TFPI2。结论：这些数据提供了与先天性CMV相关的免疫激活和胎盘功能障碍的细胞类型分辨的分子相关性。总之，数据表明先天性CMV感染与母胎界面协调性转变相关，其中广泛的干扰素驱动免疫反应伴随滋养层发育和血管程序的抑制，为更大规模的胎盘CMV传播研究提供了细胞类型分辨的参考。未来需要在更大队列中研究以确认这些发现。

英文摘要

Congenital cytomegalovirus (CMV) is the most common congenital infection and a leading infectious cause of childhood hearing loss and neurodevelopmental disability. The cellular organization of the placental response to infection is incompletely defined. We applied Visium CytAssist spatial transcriptomics to formalin-fixed tissue from two CMV-infected and two uninfected late-gestation placentas and annotated the major maternal and fetal cell populations by reference-based label transfer. Across 16,074 spatial spots, the only significant compositional changes were increased T cell spots and decreased syncytiotrophoblast-enriched spots in CMV-infected placentas; the remaining populations showed similar changes but did not reach significance. Differential expression comparing CMV-infected to uninfected samples within each cell type identified two opposing programs. Infected placentas displayed a broad interferon-stimulated gene signature accompanied by induction of CXCR3-ligand chemokines, antigen-processing machinery, and the major histocompatibility complex class I transactivator NLRC5, classical-pathway complement components, and lymphocyte and plasma-cell markers, most pronounced in endothelial, stromal, and syncytiotrophoblast clusters and minimal in extravillous trophoblasts. Concurrently, infected placentas showed downregulation of trophoblast differentiation and syncytialization genes, including PAPPA2, pregnancy-specific glycoproteins, CGA, and GCM1, as well as vascular and hemostatic genes, including FLT1, VEGFA, PECAM1, and TFPI2. These data provide a cell-type-resolved molecular correlation of immune activation and placental dysfunction associated with congenital CMV. Together, the data indicate that congenital CMV infection is associated with a coordinated shift at the maternal-fetal interface, in which a broad interferon-driven immune response accompanies suppression of trophoblast-developmental and vascular programs, providing a cell-type-resolved reference for larger studies of placental CMV transmission. Future studies in larger cohorts will be needed to confirm these findings.