Modeling Prenatal COVID-19 Exposure Using Human Cortical Organoids and Mouse Models

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Project Summary/Abstract The prevalence of neuropsychiatric disorders is increasing, constituting approximately 28% of the global burden of non-communicable disease. A major cause of these disorders is that of aberrant fetal brain development, and there is growing evidence implicating prenatal exposures as a driving factor. A common exposure that has undergone an exponential increase in incidence during recent years is that of viral infections, due in part to the novel coronavirus disease 2019 (COVID-19) pandemic. Up to 1/3 of COVID-19 patients have manifested neurological complications, and RNA from the etiologic agent SARS-CoV-2 has been found in brain biopsies from fatal cases. Furthermore, increasing rates of pre-term birth, miscarriages, and other defects have been seen following a maternal infection. The neurotropism of SARS-CoV-2 and the implications of neuroinflammation on both the adult and developing brain are still poorly understood. Therefore, it is imperative to gain insight into the mechanism(s) responsible for these complications. My central hypothesis is that SARS-CoV-2 infection and neuroinflammation trigger neurodevelopmental changes leading to a disruption of neural structure and circuit function in the developing cortex. Due to the inaccessibility of brain tissue from COVID-19 patients, I will address these questions using 3D cortical organoids differentiated from human embryonic stem cells. To elucidate the cellular effects of prenatal COVID-19 exposure on the development of the fetal brain, I will investigate the following aims: (1) determine the mechanism by which neuroinflammation influences SARS-CoV-2 infection in cortical organoids and (2) examine the neurological consequences of prenatal COVID-19 infection in humanized mice. My preliminary data revealed that compared to neuronal cells, glial cell types were more susceptible to SARS-CoV-2 infection, and that viral replication and cell death does not occur in these infected cells. Aim 1 will be to use immunostaining and functional assays to evaluate alterations in viral infection levels, viral replication, cellular integrity, and neuronal networks. In Aim 2, I hope to interrogate the effects seen in this in vitro model in an intact in utero system by infecting pregnant mice with SARS-CoV-2. Receiving this fellowship will allow me to gain novel insight into the specific cellular and molecular etiology of potential neuropsychiatric disorder development from prenatal COVID-19 exposure, as well as establish an accessible and ethically acceptable method to elucidate the underlying mechanisms of abnormal human fetal brain development, potentially contributing to future therapies and interventions.