Effects of spike protein and toxin-like peptides found in COVID-19 patients on human 3D neuronal/glial model undergoing differentiation: Possible implications for SARS-CoV-2 impact on brain development

While perinatal infections may increase the risk for the offspring to develop neurodevelopmental disorders, the possible neurodevelopmental consequences of SARS-CoV-2 are still unknown. In utero exposure to SARS-CoV-2 has been hypothesized to affect the developing brain, possibly disrupting neurodevelopment of children. Apart from the possible direct involvement of SARS-CoV-2 or its specific viral components in the occurrence of neurological and neurodevelopmental manifestations, we recently reported the presence of toxin-like peptides in plasma, urine and fecal samples specifically from COVID-19 patients. In this study, we investigated the possible neurotoxic effects elicited 72 hour after treatment with recombinant spike protein, toxin-like peptides found in COVID-19 patients, and a combination of both on 3D human iPSC-derived neural stem cells differentiated towards neurons/glia. Our data show that spike protein at non-cytotoxic concentration caused a decrease of spontaneous electrical activity after 2-day treatment. Whole transcriptome analysis revealed the dysregulation of five specific genes (SPHK1, ELN, GASK1B, HEY1 and UTS2). The perturbations of these neurodevelopmental endpoints are discussed in the context of recent knowledge about the key events described in Adverse Outcome Pathways relevant to COVID-19, gathered in the context of the CIAO project.

PISTOLLATO Francesca;  PETRILLO Mauro;  CLERBAUX Laure-Alix;  LEONI Gabriele;  PONTI Jessica;  BOGNI Alessia;  BROGNA Carlo;  CRISTONI Simone;  SANGES Remo;  MENDOZA Emilio;  FABBRI Marco;  QUERCI Maddalena;  SOARES Helena;  MUNOZ-PINEIRO Maria Amalia;  WHELAN Maurice;  VAN DEN EEDE Guy; 

2022-06-15

PERGAMON-ELSEVIER SCIENCE LTD

JRC127446

0890-6238 (online),   

https://www.sciencedirect.com/science/article/pii/S0890623822000600,    https://publications.jrc.ec.europa.eu/repository/handle/JRC127446,   

10.1016/j.reprotox.2022.04.011 (online),