Dysregulation of brain and choroid plexus cell types in severe COVID-19.

Yang, Andrew C; Kern, Fabian; Losada, Patricia M; Agam, Maayan R; Maat, Christina A; Schmartz, Georges P; Fehlmann, Tobias; Stein, Julian A; Schaum, Nicholas; Lee, Davis P; Calcuttawala, Kruti; Vest, Ryan T; Berdnik, Daniela; Lu, Nannan; Hahn, Oliver; Gate, David; McNerney, M Windy; Channappa, Divya; Cobos, Inma; Ludwig, Nicole; Schulz-Schaeffer, Walter J; Keller, Andreas; Wyss-Coray, Tony

Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1-3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4-6. Synaptic signaling of upper-layer excitatory neurons-evolutionarily expanded in humans7 and linked to cognitive function8-are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.