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

Andrew C. Yang, Fabian Kern, Patricia M. Losada, Maayan R. Agam, Christina A. Maat, Georges P. Schmartz, Tobias Fehlmann, Julian A. Stein, Nicholas Schaum, Davis P. Lee, Kruti Calcuttawala, Ryan T. Vest, Daniela Berdnik, Nannan Lu, Oliver Hahn, David Gate, M. Windy McNerney, Divya Channappa, Inma Cobos, Nicole Ludwig, Walter J. Schulz-Schaeffer, Andreas Keller () and Tony Wyss-Coray ()
Additional contact information
Andrew C. Yang: Stanford University School of Medicine
Fabian Kern: Saarland University
Patricia M. Losada: Stanford University School of Medicine
Maayan R. Agam: Stanford University School of Medicine
Christina A. Maat: Stanford University School of Medicine
Georges P. Schmartz: Saarland University
Tobias Fehlmann: Saarland University
Julian A. Stein: Saarland University Hospital and Medical Faculty of Saarland University
Nicholas Schaum: Stanford University School of Medicine
Davis P. Lee: Stanford University School of Medicine
Kruti Calcuttawala: Stanford University School of Medicine
Ryan T. Vest: Stanford University School of Medicine
Daniela Berdnik: Stanford University School of Medicine
Nannan Lu: Stanford University School of Medicine
Oliver Hahn: Stanford University School of Medicine
David Gate: Stanford University School of Medicine
M. Windy McNerney: Stanford University School of Medicine
Divya Channappa: Stanford University School of Medicine
Inma Cobos: Stanford University School of Medicine
Nicole Ludwig: Saarland University
Walter J. Schulz-Schaeffer: Saarland University Hospital and Medical Faculty of Saarland University
Andreas Keller: Stanford University School of Medicine
Tony Wyss-Coray: Stanford University

Nature, 2021, vol. 595, issue 7868, 565-571

Abstract: Abstract Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1–3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4–6. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans7 and linked to cognitive function8—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found 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 current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.

Date: 2021
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DOI: 10.1038/s41586-021-03710-0

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