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

Samudyata,; Oliveira, Ana Osório; Malwade, Susmita; Rufino de Sousa, Nuno; Goparaju, Sravan K; Orhan, Funda; Steponaviciute, Laura; Sheridan, Steven D; Perlis, Roy H.; Rothfuchs, Antonio; Sellgren, Carl M.

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.