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

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.

Direct and indirect impact of SARS-CoV-2 on the brain

“…At first, the data corroborated many of the findings in brain organoids (Jacob et al 2020 ) and in mice (Kumari et al 2021 ; Song et al 2021b ; Rothan et al 2022 ), showing a robust enrichment in the expression of genes of innate immunity and, as expected, a significant impact on the CP (Yang et al 2021 ) which was further, corroborated in multiple sclerosis patients with COVID-19 (Fuchs et al 2021 ). It also confirmed other research that claimed the absence of neuroinvasion (Fernández-Castañeda et al 2022 ) although with important microglial activation (Samudyata et al 2022 ; Beckman et al 2022 ).…”

“…For this reason, most in vitro studies used primary cells either from K18-ACE-2 transgenic mice, hamsters (Rothan et al 2022 ; de Oliveira et al 2022 ) or wild-type animals pre-treated with an adenovirus (AAV-hACE-2) as a vector to induce the expression of hACE-2 (Song et al 2021b ; Monje and Iwasaki 2022 ). Other studies also used human-derived induced-pluripotent stem cells (iPSCs) as well as brain organoids (Ramani et al 2020 , 2021 ; Jacob et al 2020 ; Song et al 2021b ; Samudyata et al 2022 ; Kong et al 2022 ), which are useful tools for the study of many aspects of brain development, function, metabolism and has already been used for the studies of other viral infection, including ZIKA virus (Cugola et al 2016 ), dengue virus, influenza virus and also SARS-CoV-2, as reviewed (Harschnitz and Studer 2021 ).…”

“…Recent research performing a secretome analysis demonstrated that whereas other cell types reduced cellular interactions after SARS-CoV-2 infection, CP gained (Samudyata et al 2022 ). Interestingly, most of these interactions correlated with extracellular matrix, barrier maintenance and solute homeostasis, confirming findings in the human brain (Yang et al 2021 ).…”

Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”

“…In only 10 of 133 reported series focusing upon the diagnosis and treatment of patients diagnosed with immune-mediated symptoms of COVID-19, were specific neuronal or ganglioside antibodies identified [ 57 ]. Another putative mechanism utilized a newly established brain organoid model with innately developing microglia, which upon exposure to COVID-19 infection induced neuronal cell death due to microglial post synaptic terminal elimination [ 72 ].…”

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…Encephalitis is well documented, usually in hospitalized COVID-19 patients with severe disease, with encephalitis predisposing to poor outcomes and a higher risk of mortality 9,[24][25][26] . The mechanism(s) whereby brain pathology/immunopathology and/or neuropathology might manifest in COVID-19 patients remains debatable, with the systemic cytokine storm and/or direct brain infection likely involved 22,[27][28][29][30][31][32] . A number of studies have now shown brain infection in COVID-19 patients [33][34][35][36][37] , with viral RNA or protein detected in the brains of 20-38% of patients that died of COVID-19 38,39 .…”