胎盘感染在先天性人巨细胞病毒(HCMV)感染的发病机理中起着重要作用,并且是胎儿生长受限和妊娠丢失的原因。HCMV可以在某些滋养层细胞类型中复制,但目前尚不清楚该病毒如何逃避胎盘中的抗病毒免疫,以及感染如何损害胎盘的发育和功能。人滋养层干细胞(TSCs)可以分化为绒毛外滋养层(EVTs),合胞体滋养层(STBs),和类器官,这项研究评估了TSCs作为孕早期胎盘HCMV感染模型的实用性。发现HCMV非生产性感染TSCs,EVT,和STBs。免疫荧光测定和流式细胞术实验进一步揭示,感染的TSC通常仅表达立即早期病毒基因产物。同样,RNA测序发现TSC中的病毒基因表达不遵循成纤维细胞中裂解感染期间观察到的动力学模式。在HCMV感染的TSC和TSC衍生的滋养层中大部分未观察到典型的抗病毒反应。相反,与细胞身份有关的感染失调因子,分化,和无翼/集成信令。因此,虽然HCMV不在TSC中复制,感染可能会以可能干扰胎盘功能的方式干扰滋养细胞的分化。
目的:胎盘感染在妊娠期人巨细胞病毒(HCMV)发病机制中起着重要作用,但是HCMV的物种特异性以及初级滋养细胞的有限可用性和寿命一直是理解感染如何影响这一重要器官的持续障碍。人滋养层干细胞(TSCs)代表了一种在胎盘发育早期对病毒感染进行建模的新方法。这项研究表明,TSCs,像其他干细胞类型一样,限制HCMV复制。然而,感染扰乱了参与分化和细胞命运决定的基因的表达,指出HCMV可能导致胎盘损伤的机制。
Placental infection plays a central role in the pathogenesis of congenital human cytomegalovirus (HCMV) infections and is a cause of fetal growth restriction and pregnancy loss. HCMV can replicate in some trophoblast cell types, but it remains unclear how the virus evades antiviral immunity in the placenta and how infection compromises placental development and function. Human trophoblast stem cells (TSCs) can be differentiated into extravillous trophoblasts (EVTs), syncytiotrophoblasts (STBs), and organoids, and this study assessed the utility of TSCs as a model of HCMV infection in the first-trimester placenta. HCMV was found to non-productively infect TSCs, EVTs, and STBs. Immunofluorescence assays and flow cytometry experiments further revealed that infected TSCs frequently only express immediate early viral gene products. Similarly, RNA sequencing found that viral gene expression in TSCs does not follow the kinetic patterns observed during lytic infection in fibroblasts. Canonical antiviral responses were largely not observed in HCMV-infected TSCs and TSC-derived trophoblasts. Rather, infection dysregulated factors involved in cell identity, differentiation, and Wingless/Integrated signaling. Thus, while HCMV does not replicate in TSCs, infection may perturb trophoblast differentiation in ways that could interfere with placental function.
OBJECTIVE: Placental infection plays a central role in human cytomegalovirus (HCMV) pathogenesis during pregnancy, but the species specificity of HCMV and the limited availability and lifespan of primary trophoblasts have been persistent barriers to understanding how infection impacts this vital organ. Human trophoblast stem cells (TSCs) represent a new approach to modeling viral infection early in placental development. This study reveals that TSCs, like other stem cell types, restrict HCMV replication. However, infection perturbs the expression of genes involved in differentiation and cell fate determination, pointing to a mechanism by which HCMV could cause placental injury.