Abdelbasset Muhammad, Saron Wilfried A A, Ma Dongliang, Rathore Abhay P S, Kozaki Tatsuya, Zhong Chengwei, Mantri Chinmay Kumar, Tan Yingrou, Tung Chi-Ching, Tey Hong Liang, Chu Justin Jang Hann, Chen Jinmiao, Ng Lai Guan, Wang Hongyan, Ginhoux Florent, St John Ashley L
Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.
Cell. 2024 Dec 26;187(26):7511-7532.e20. doi: 10.1016/j.cell.2024.10.028. Epub 2024 Nov 11.
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.
先天性感染期间胎儿免疫细胞的功能尚不清楚。寨卡病毒（ZIKV）可从母亲垂直传播给胎儿，导致神经系统感染和先天性寨卡病毒综合征（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。来自卵黄囊的ZIKV感染的原始巨噬细胞的转运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，脑内驻留的分化小胶质细胞具有保护作用，限制感染和神经元死亡。单细胞RNA测序确定了与单核吞噬细胞亚群的保护与有害作用相关的转录谱。在人脑类器官中，小胶质细胞也促进了神经保护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，这与原始巨噬细胞和单核细胞的疾病增强作用形成对比。基因不同的ZIKV对髓样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。
