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.