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

Abstract

Neuropsychiatric manifestations are common in both acute and post-acute phase of SARS-CoV-2 infection, but the mechanism of these effects is unknown. Here, we derive human brain organoids with innately developing microglia to investigate the cellular responses to SARS-CoV-2 infection on a single cell level. We find evidence of limited tropism to SARS-CoV-2 for all major cell types and observe extensive neuronal cell death that also include non-infected cells. Single cell transcriptome profiling reveals distinct responses in microglia and astrocytes that share features with cellular states observed in neurodegenerative diseases, includes upregulation of genes with relevance for synaptic stripping, and suggests altered blood brain barrier integrity. Across all cell types, we observe a global translational shut-down as well as altered carbohydrate metabolism and cellular respiration. Together, our findings provide insights into cellular responses of the resident brain immune cells to SARS-CoV-2 and pinpoint mechanisms that may be of relevance for the neuropathological changes observed in COVID-19 patients.

SARS-CoV-2 spike protein induces TLR-4-mediated long-term cognitive dysfunction recapitulating post-COVID syndrome

“…Likewise, we found that the late cognitive dysfunction induced by S was accompanied by prominent synapse loss in mice hippocampus. Recent data have revealed the upregulation of genes linked to synapse elimination in SARS-CoV-2-infected human brain organoids and in post-mortem samples from COVID-19 patients(Samudyata et al, 2022; Yang et al, 2021). In line, we found that infusion of S into mouse brain induces a late elevation in plasma levels of NFL, an axonal cytoskeleton protein recently identified as a component of pre- and postsynaptic terminals(Yuan et al, 2015).…”

Microglia-containing human brain organoids for the study of brain development and pathology

“…By using MC-HBOs, the ALS-PDC study [94] revealed that the shift of microglia to a more pro-inflammatory state, which exacerbated inflammation and reduced extracellular matrix strength, may account for the etiology of ALS-PDC. Unlike previous studies [91][92][93], this study didn't reduce the concentration of heparin to 0.1 ug/mL but also resulted into microglia generation in cerebral organoids.…”

“…Based on the protocol of Ormel et al [91], other studies [92-94] also generated HBOs containing innately-developed microglia. The MC-HBOs were used to model SARS-CoV-2 infection [93] or Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC, a neurodegenerative disease) [94]. Upon SARS-CoV-2 infection, the innately-developed microglia in organoids responded to viral infection through upregulating phagocytosisand interferon-related pathways.…”

“…Upon SARS-CoV-2 infection, the innately-developed microglia in organoids responded to viral infection through upregulating phagocytosisand interferon-related pathways. Several AD and multiple sclerosis susceptibility genes were also found to be upregulated in microglia upon SARS-CoV-2 infection, suggesting potential contribution of SARS-CoV-2 to neurological symptoms [93]. By using MC-HBOs, the ALS-PDC study [94] revealed that the shift of microglia to a more pro-inflammatory state, which exacerbated inflammation and reduced extracellular matrix strength, may account for the etiology of ALS-PDC.…”

Neurodevelopmental disorders—high-resolution rethinking of disease modeling

“…By further reducing neuroectoderm stimulation, mesoderm-derived progenitors have, however, been shown to emerge spontaneously in undirected organoids and display microglia markers at later time points [ 67 ]. Single-cell transcriptomic profiling of such microglia-like cells at later stages has also shown a convincing clustering with fetal microglia [ 68 ]. Given the general limitations of less guided protocols, such as more pronounced organoid-to-organoid variability and relatively low and variable microglia counts, other approaches have also been proposed, such as adding mesodermal yolk sac progenitors to patterned brain region-specific organoids [ 69 ] or adding iPSC-derived microglia to undirected organoids [ 70 ].…”