Cellular models of fetal neurodevelopment in maternal SARS-CoV-2 infection

PROJECT SUMMARY The impact of maternal SARS-CoV-2 infection on the developing fetus remains unknown, but preliminary data has begun to accumulate suggesting neurodevelopmental effects in offspring. There is compelling evidence that the fetal brain is particularly vulnerable to maternal immune activation and inflammatory exposures during key developmental windows. In light of the projection that millions of fetuses will ultimately be exposed to COVID- 19, understanding and modeling this risk is a pressing scientific and public health concern. While long-term clinical outcomes cannot be known for a decade or more, tools to model risk for adverse neurodevelopmental outcomes, understand mechanisms of risk, and to screen for interventions, are urgently needed. Microglia, the resident brain immune cells, play a critical role in normal brain development, and are known to be impacted by the intrauterine environment. The investigators have developed and validated methods to efficiently generate human microglia-like cells from peripheral blood, including umbilical cord blood. They demonstrated previously that these cells recapitulate morphology, transcriptome, and function of microglia derived from postmortem brain. Further, these models identify schizophrenia-associated pruning dysfunction, using a scalable synaptosome model as well as long-term co-culture. Here, the investigators propose to characterize effects of maternal SARS-CoV-2 infection using the large biospecimen bank they have created that includes matched maternal blood and neonatal cord blood, linked to abundant clinical detail and electronic health records. The bank includes more than 800 neonates of mothers who are SARS-CoV-2 positive (547), or SARS-CoV-2 negative and pregnant during the pandemic (265). Specifically, the investigators will characterize maternal immune activation via multiple cellular and serum measures. They will then create personalized neonatal models of microglial function using banked umbilical cord blood mononuclear cells. They will compare morphologic, transcriptomic, and functional differences between induced microglial cells from SARS-CoV-2-exposed and unexposed neonates, to test the hypothesis that SARS- CoV-2-related maternal immune activation primes microglial cells in utero toward an inflammatory phenotype, leading to dysregulated neurodevelopment. Finally, they will create an electronic health records cohort of more than 10,000 deliveries to examine risk for neurodevelopmental diagnoses among offspring of SARS-CoV-2 positive compared to negative mothers, ultimately capturing up to 5 years of follow-up. Together, these experiments will quantify the potential impact of maternal viral infection and immune activation on the developing fetal brain, examine a potential biomarker of risk, and develop a model system that may be used to identify and test interventions to minimize such risk. The project integrates laboratories with expertise in the impact of environmental exposures on maternal immune activation and developmental outcomes, patient-derived in vitro cellular modeling, and analysis of longitudinal electronic health records.