Fetal immune cell functions during congenital infections are poorly understood. Zika virus (ZIKV) can vertically transmit from mother to fetus, causing nervous system infection and congenital ZIKV syndrome (CZS). We identified differential functional roles for fetal monocyte/macrophage cell types and microglia in ZIKV dissemination versus clearance using mouse models. Trafficking of ZIKV-infected primitive macrophages from the yolk sac allowed initial fetal virus inoculation, while recruited monocytes promoted non-productive neuroinflammation. Conversely, brain-resident differentiated microglia were protective, limiting infection and neuronal death. Single-cell RNA sequencing identified transcriptional profiles linked to the protective versus detrimental contributions of mononuclear phagocyte subsets. In human brain organoids, microglia also promoted neuroprotective transcriptional changes and infection clearance. Thus, microglia are protective before birth, contrasting with the disease-enhancing roles of primitive macrophages and monocytes. Differential modulation of myeloid cell phenotypes by genetically divergent ZIKVs underscores the potential of immune cells to regulate diverse outcomes during fetal infections.

中文翻译：

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先天性感染期间胎儿单核吞噬细胞对寨卡病毒神经侵袭与神经保护作用的不同贡献


对先天性感染期间的胎儿免疫细胞功能知之甚少。寨卡病毒 （ZIKV） 可以从母亲垂直传播给胎儿，导致神经系统感染和先天性 ZIKV 综合征 （CZS）。我们使用小鼠模型确定了胎儿单核细胞/巨噬细胞类型和小胶质细胞在 ZIKV 传播与清除中的不同功能作用。从卵黄囊中运输 ZIKV 感染的原始巨噬细胞允许初始胎儿病毒接种，而募集的单核细胞促进非生产性神经炎症。相反，大脑驻留的分化小胶质细胞具有保护性，限制了感染和神经元死亡。单细胞 RNA 测序确定了与单核吞噬细胞亚群的保护性与有害性贡献相关的转录谱。在人脑类器官中，小胶质细胞还促进神经保护性转录变化和感染清除。因此，小胶质细胞在出生前具有保护作用，与原始巨噬细胞和单核细胞的疾病增强作用形成鲜明对比。遗传差异 ZIKV 对骨髓细胞表型的差异调节强调了免疫细胞在胎儿感染期间调节不同结果的潜力。