Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.

母体 COVID-19 感染增加了后代神经发育障碍 （NDD） 的发病率，尽管其潜在机制尚未阐明。这项研究表明，怀孕期间的 COVID-19 感染破坏了母体和胎儿免疫环境的平衡，推动了星形胶质细胞、内皮细胞和兴奋性神经元的改变。使用妊娠母亲单细胞转录组中的 47 个独特基因建立风险评分。CD4 增殖 T 细胞水平的高风险评分作为后代 NDD 风险增加的指标。进行了基于总结的孟德尔随机化和表型组范围关联研究分析，以确定转录变化与后代 NDD 风险增加的因果关系。此外，10 种药物被确定为潜在的治疗候选药物。我们的研究结果支持一个模型，在该模型中，母体 COVID-19 感染改变了 CD4 增殖 T 细胞的水平，导致后代星形胶质细胞、内皮细胞和兴奋性神经元的改变，从而导致这些个体患 NDD 的风险增加。