Human Trophoblast Stem Cells Restrict Human Cytomegalovirus Replication.
Human Trophoblast Stem Cells Restrict Human Cytomegalovirus Replication.
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人类滋养层干细胞限制人类巨细胞病毒复制。
DOI：
10.1101/2023.12.13.571456
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bierle,CraigJ
中科院分区：
文献类型：
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作者：
Rollman,TylerB;Berkebile,ZacharyW;Okae,Hiroaki;Bardwell,VivianJ;Gearhart,MicahD;Bierle,CraigJ
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，但仍不清楚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。人滋养层干细胞（TSC）可以分化为绒毛外滋养层细胞（EVT），合胞体滋养层细胞（STB）和类器官，本研究评估了TSC作为早期妊娠胎盘中HCMV感染模型的实用性。发现HCMV非生产性地感染TSC、EVT和STB。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。类似地，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衍生的滋养层细胞中基本上没有观察到典型的抗病毒反应。相反，感染失调的因素涉及细胞的身份，分化，和无翅/集成信号。因此，虽然HCMV不复制的TSCs，感染可能扰乱滋养层细胞分化的方式，可能会干扰胎盘function.IMPORTANCEPlacental感染起着核心作用，在人巨细胞病毒（HCMV）的发病机制在怀孕期间，但HCMV的物种特异性和有限的可用性和初级滋养层细胞的寿命一直是持久的障碍，以了解感染如何影响这个重要的器官。人滋养层干细胞（TSCs）代表了一种新的方法来模拟胎盘发育早期的病毒感染。这项研究表明，像其他干细胞类型一样，TSCs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.IMPORTANCEPlacental 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.