Modeling the Neurological Effects and Implications of Prenatal Covid-19 Exposure
The global burden of neuropsychiatric disorders is increasing, with a major cause being aberrant fetal brain development. There is growing evidence implicating prenatal exposures, and an increasingly common exposure is that of viral infections, due in part to the COVID-19 pandemic. Around 50% of COVID-19 cases have manifested neurological complications, with up to 20% suffering from "long-COVID" complications. Furthermore, there have been increasing rates of complications with birth and pregnancy following a maternal case. Still poorly understood, however, are the consequences of SARS-CoV-2 infection on the brain, in particular the developing brain, as well as the potential for viral transmission to the fetus. Therefore, it is imperative to gain insight into the mechanism(s) responsible for such complications. In this work, I show that SARS-CoV-2 does infect cells of the CNS both in vitro and in vivo. Using hESC-derived cortical organoids, my data revealed that choroid plexus cells and glia such as astrocytes and radial glia, were much more susceptible to SARS-CoV-2 infection than neurons, however, viral replication and infection-induced cell death did not occur in this model system. Additionally, I explored the influence of inflammatory molecules on infection in this model; however, I observed no significant changes. Finally, I investigated the consequences of SARS-CoV-2 infection on the developing brain in an in utero system using human ACE2 knock-in mice. I found that pregnant mice displayed more severe COVID-19 infections than non-pregnant mice, and that viral transmission to the fetus did occur at later developmental stages (>E16.5). Infection primarily targeted male fetuses, and was dependent on hACE2 binding in these mice. Interestingly, viral dissemination primarily occurred through the fetal circulatory system, with SARS-CoV-2 detection largely in the blood vessels of the brain. Additionally, various critical cells of the fetal brain such as glia, neurons, and choroid plexus cells were targeted. No increase in maternal inflammation was observed in these mice following infection however, despite showing signs of disease. Overall, these findings have concerning implications regarding neurodevelopment following prenatal COVID-19 exposure.