Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection

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.