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 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.
Source: Samudyata, Oliveira AO, Malwade S, Rufino de Sousa N, Goparaju SK, Gracias J, Orhan F, Steponaviciute L, Schalling M, Sheridan SD, Perlis RH, Rothfuchs AG, Sellgren CM. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol Psychiatry. 2022 Oct 5:1–12. doi: 10.1038/s41380-022-01786-2. Epub ahead of print. PMID: 36198765; PMCID: PMC9533278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533278/ (Full text)