Human neural stem cells that help form the brain and spinal cord are highly susceptible to SARS-CoV-2, including Omicron variants BA.1 and BA.2, according to new research from the University of California, Riverside. The findings raise concerns about the potential effects of maternal COVID-19 infection on early nervous system development and underscore the importance of monitoring children exposed to the virus before birth.
The researchers, led by Prue Talbot, a professor of the graduate division in the Department of Molecular, Cell and Systems Biology, found that human neural stem cells were significantly more susceptible to infection by SARS-CoV-2 spike pseudoparticles pseudoparticles — modified, non-replicating virus particles used to safely study infection — than undifferentiated human embryonic stem cells. The susceptibility was observed with the original viral spike as well as the two Omicron variants.
“Our data clearly show that human neural stem cells are readily infected by SARS-CoV-2 pseudovirus, including the currently prevalent Omicron variants,” Talbot said.
Neural stem cells emerge from the ectoderm, an early embryonic tissue that gives rise to the central nervous system. Because these cells help establish the foundation for the brain and spinal cord, infection during early development could have consequences ranging from pregnancy loss and severe developmental abnormalities to more subtle changes that may not be apparent at birth.
“Such subtle damage might only appear years later as learning, behavioral, or cognitive difficulties,” said Ann Song, a postdoctoral researcher in Talbot’s lab and the first author of the study published in PLOS One.
The transmission of SARS-CoV-2 from mother to fetus has been documented, including during the first trimester. Children exposed to the virus in utero are now reaching ages at which potential neurodevelopmental differences can be assessed. The researchers also noted that their findings are consistent with a large health-record study linking maternal SARS-CoV-2 infection to an increased risk of a neurodevelopmental diagnosis in children by age 3.
To investigate how the virus might enter developing neural cells, the team differentiated human embryonic stem cells into neural stem cells and exposed them to the pseudoparticles.
The experiments showed that Omicron pseudoparticles entered neural stem cells primarily through endocytosis, a process in which cells engulf external material. The researchers found that blocking this pathway with the compound filipin reduced viral entry by approximately 75% to 85%.
The team also found that neural stem cells have a relatively sparse layer of sugar molecules on their surfaces. Removing these sugar groups increased pseudoparticle entry twofold to fourfold, suggesting that the cell-surface sugar layer may help limit viral access.
The research addresses a question that cannot readily be investigated through experiments in pregnant women: whether early precursors of the nervous system are vulnerable to SARS-CoV-2. Although fetal transmission has been documented, the susceptibility of these early developmental cells has been less clear.
“Our data emphasize the need for monitoring children exposed in utero to SARS-CoV-2 for evidence of deficiencies in the central nervous system,” Song said.
Talbot said the findings do not establish that infection of neural stem cells by the pseudovirus causes neurological harm in human pregnancies.
“Further research will be needed to determine whether and how infection at these early stages affects brain development,” she said.
The study was funded by a UCR Academic Senate Committee on Research grant, an Academic Merit Fellowship, a Yvonne Danielson Endowed Graduate Award, a UCR Graduate Division Dissertation Completion Fellowship Award, and the Tobacco-Related Disease Research Program.
Talbot and Song were joined in the research by Cori Zuvia, a doctoral student in the UCR Neuroscience Graduate Program.
The title of the paper is “Susceptibility of human neural stem cells to SARS-CoV-2: Entry mechanisms and glycocalyx influence.”
