SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

Author:

Samudyata ,Oliveira Ana O.,Malwade Susmita,Rufino de Sousa Nuno,Goparaju Sravan K.,Gracias Jessica,Orhan Funda,Steponaviciute Laura,Schalling MartinORCID,Sheridan Steven D.ORCID,Perlis Roy H.,Rothfuchs Antonio G.ORCID,Sellgren Carl M.ORCID

Abstract

AbstractNeuropsychiatric 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 initiate neuronal cell death and cause a 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 synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 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.

Funder

Svenska Forskningsrådet Formas

Karolinska Institutet

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Psychiatry and Mental health,Molecular Biology

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