Impact of SARS-CoV-2 infection on the central nervous system – isiBrain

The current COVID-19 pandemic put the world in an unprecedented situation, with a wide influence on our daily lives. Increasing evidence indicates that short- and long-term neurological complications are associated to SARS-CoV-2 infection. However, minimal information regarding the impact of the virus on the central nervous system is available. In particular, the lack of mechanistic insights dampens our understanding of the COVID-19-induced neuropathological features (neuroCOVID), thus preventing the elaboration of suitable treatments. Here, we propose to determine the molecular and cellular impact of SARS-CoV-2 on the human brain cortex using human stem-cell-derived cerebral organoids and organotypic culture of post-mortem human brain slices. We will first fully characterize these models and evaluate the permissiveness and replication kinetic profiles of SARS-CoV-2 in the major neural cell types. In parallel, we will investigate how SARS-CoV-2 infection and/or exposure affects neurological synapse formation and monitor the perturbation of neuronal electrical activity. Finally, differential proteomics on single organoids allowed us to identify a subset of host factors significantly modulated upon SARS-CoV-2 infection and we will decipher the consequences of protein expression perturbation in order to find the origin of neurological dysfunctions in infected patients. Together, this work shall provide seminal knowledge regarding the molecular mechanisms leading to SARS-CoV-2-induced neurological disorders.