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, Tony Wyss-Coray
Author Information
Andrew C Yang: Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. ORCID
Julian A Stein: Institute for Neuropathology, Saarland University Hospital and Medical Faculty of Saarland University, Homburg, Germany.
Nicholas Schaum: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Davis P Lee: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Kruti Calcuttawala: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Ryan T Vest: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Daniela Berdnik: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Nannan Lu: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Oliver Hahn: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
David Gate: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. ORCID
M Windy McNerney: Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA.
Divya Channappa: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Inma Cobos: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Nicole Ludwig: Department of Human Genetics, Saarland University, Homburg, Germany.
Walter J Schulz-Schaeffer: Institute for Neuropathology, Saarland University Hospital and Medical Faculty of Saarland University, Homburg, Germany. ORCID
Andreas Keller: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. andreas.keller@ccb.uni-saarland.de. ORCID
Tony Wyss-Coray: ChEM-H, Stanford University, Stanford, CA, USA. twc@stanford.edu. ORCID
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms. 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 disease. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans and linked to cognitive function-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.
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