SARS-CoV-2 Neurotropism and Single Cell Responses in Brain Organoids Containing Innately Developing Microglia

Samudyata,; Oliveira, A. O.; Malwade, S.; de Sousa, N. R.; Goparaju, S. K.; Orhan, F.; Steponaviciute, L.; Sheridan, S. D.; Perlis, R. H.; Rothfuchs, A. G.; Sellgren-Majkowitz, C.

doi:10.1101/2021.07.07.451463

bioRxiv · 10.1101/2021.07.07.451463

SARS-CoV-2 Neurotropism and Single Cell Responses in Brain Organoids Containing Innately Developing Microglia

Samudyata,·Oliveira, A. O.·Malwade, S.·de Sousa, N. R.·Goparaju, S. K.·Orhan, F.·Steponaviciute, L.·Sheridan, S. D.·Perlis, R. H.·Rothfuchs, A. G.·Sellgren-Majkowitz, C.

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Abstract

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection causes an extensive cell death and loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synaptic stripping. To a large extent, SARS-CoV-2 exposed microglia display a transcriptomic profile previously observed in neurodegenerative disorders characterized by early a synapse loss and an increased incident risk after a Covid-19 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from Covid-19.

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Samudyata,, Oliveira, A. O., Malwade, S., de Sousa, N. R., Goparaju, S. K., Orhan, F., Steponaviciute, L., Sheridan, S. D., Perlis, R. H., Rothfuchs, A. G., Sellgren-Majkowitz, C.. 2021-07-08. SARS-CoV-2 Neurotropism and Single Cell Responses in Brain Organoids Containing Innately Developing Microglia. https://doi.org/10.1101/2021.07.07.451463

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