Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Informative Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Virol. 2024 Apr 16;98(4):e0193523. doi: 10.1128/jvi.01935-23. Epub 2024 Mar 7.
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.
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.
胎盘感染在先天性人巨细胞病毒（HCMV）感染的发病机制中起核心作用，是导致胎儿生长受限和妊娠丢失的原因。HCMV 可以在一些滋养细胞类型中复制，但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发育和功能仍不清楚。人滋养层干细胞（TSC）可分化为绒毛外滋养细胞（EVT）、合体滋养细胞（STB）和类器官，本研究评估了 TSC 作为妊娠早期胎盘 HCMV 感染模型的效用。发现 HCMV 可非生产性感染 TSC、EVT 和 STB。免疫荧光和流式细胞术实验进一步表明，感染的 TSC 通常仅表达即刻早期病毒基因产物。同样，RNA 测序发现 TSC 中的病毒基因表达不符合在成纤维细胞中溶细胞感染时观察到的动力学模式。在 HCMV 感染的 TSC 和 TSC 衍生的滋养细胞中，未观察到经典的抗病毒反应。相反，感染失调了与细胞身份、分化和 Wingless/Integrated 信号相关的因素。因此，尽管 HCMV 不在 TSC 中复制，但感染可能以干扰胎盘功能的方式扰乱滋养细胞分化。
胎盘感染在妊娠期间的人巨细胞病毒（HCMV）发病机制中起核心作用，但 HCMV 的种属特异性以及原代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（TSC）代表了一种新的方法来模拟早期胎盘发育中的病毒感染。本研究表明，TSC 与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，这表明 HCMV 可能导致胎盘损伤的一种机制。
