Susceptibility of Human Neural Stem Cells to SARS-CoV-2: Entry Mechanisms and Glycocalyx Influence

Previous work demonstrated that ectodermal cells exhibit greater susceptibility to SARS-CoV-2 infection than endodermal and mesodermal cells, raising concerns about potential vulnerability of the developing nervous system. We hypothesized that neural stem cells (NSCs) derived from human ectoderm are susceptible to SARS-CoV-2 infection. Using pseudotyped viral particles representing both wild-type and Omicron spike variants, we confirmed efficient infection of NSCs, with Omicron variants preferentially utilizing endocytosis-mediated entry. Inhibition of endocytosis with filipin and OcTMAB significantly reduced infection across all spike variants. Low glycosylation levels on NSCs facilitated viral entry, and enzymatic removal of glycosylation increased their susceptibility. Ectodermal infection by SARS-CoV-2 raises serious concern for potential teratogenic effects on the nervous system, possibly causing latent or subclinical anomalies not immediately evident at birth. Therefore, future clinical studies and long-term surveillance of infants and children exposed in utero are necessary to investigate and identify potential neurodevelopmental deficits.