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

doi:10.1038/s41586-021-03710-0

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 LudwigWalter J. Schulz-Schaeffer, Andreas Keller, Tony Wyss-Coray^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

430 Scopus citations

Abstract

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms^1–3. 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 disease^4–6. 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.

Original language	English (US)
Pages (from-to)	565-571
Number of pages	7
Journal	Nature
Volume	595
Issue number	7868
DOIs	https://doi.org/10.1038/s41586-021-03710-0
State	Published - Jul 22 2021

Funding

Acknowledgements We thank N. Khoury, T. Iram, E. Tapp and other members of the laboratories of T.W.-C. and A.K. for feedback and support, and H. Zhang and K. Dickey for laboratory management. This work was funded by the NOMIS Foundation (T.W.-C.), the National Institute on Aging (T32-AG0047126 to A.C.Y. and 1RF1AG059694 to T.W.-C.), Nan Fung Life Sciences (T.W.-C.), the Bertarelli Brain Rejuvenation Sequencing Cluster (an initiative of the Stanford Wu Tsai Neurosciences Institute) and the Stanford Alzheimer’s Disease Research Center (P30 AG066515). A.C.Y. was supported by a Siebel Scholarship. F.K., G.P.S., T.F., W.J.S.-S. and A.K. are a part of the CORSAAR study supported by the State of Saarland, the Saarland University and the Rolf M. Schwiete Stiftung.

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Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M. W., Channappa, D., Cobos, I., ... Wyss-Coray, T. (2021). Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 595(7868), 565-571. https://doi.org/10.1038/s41586-021-03710-0

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title = "Dysregulation of brain and choroid plexus cell types in severe COVID-19",

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.",

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

note = "Funding Information: Acknowledgements We thank N. Khoury, T. Iram, E. Tapp and other members of the laboratories of T.W.-C. and A.K. for feedback and support, and H. Zhang and K. Dickey for laboratory management. This work was funded by the NOMIS Foundation (T.W.-C.), the National Institute on Aging (T32-AG0047126 to A.C.Y. and 1RF1AG059694 to T.W.-C.), Nan Fung Life Sciences (T.W.-C.), the Bertarelli Brain Rejuvenation Sequencing Cluster (an initiative of the Stanford Wu Tsai Neurosciences Institute) and the Stanford Alzheimer{\textquoteright}s Disease Research Center (P30 AG066515). A.C.Y. was supported by a Siebel Scholarship. F.K., G.P.S., T.F., W.J.S.-S. and A.K. are a part of the CORSAAR study supported by the State of Saarland, the Saarland University and the Rolf M. Schwiete Stiftung. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = jul,

day = "22",

doi = "10.1038/s41586-021-03710-0",

language = "English (US)",

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Yang, AC, Kern, F, Losada, PM, Agam, MR, Maat, CA, Schmartz, GP, Fehlmann, T, Stein, JA, Schaum, N, Lee, DP, Calcuttawala, K, Vest, RT, Berdnik, D, Lu, N, Hahn, O, Gate, D, McNerney, MW, Channappa, D, Cobos, I, Ludwig, N, Schulz-Schaeffer, WJ, Keller, A & Wyss-Coray, T 2021, 'Dysregulation of brain and choroid plexus cell types in severe COVID-19', Nature, vol. 595, no. 7868, pp. 565-571. https://doi.org/10.1038/s41586-021-03710-0

TY - JOUR

T1 - Dysregulation of brain and choroid plexus cell types in severe COVID-19

AU - Yang, Andrew C.

AU - Kern, Fabian

AU - Losada, Patricia M.

AU - Agam, Maayan R.

AU - Maat, Christina A.

AU - Schmartz, Georges P.

AU - Fehlmann, Tobias

AU - Stein, Julian A.

AU - Schaum, Nicholas

AU - Lee, Davis P.

AU - Calcuttawala, Kruti

AU - Vest, Ryan T.

AU - Berdnik, Daniela

AU - Lu, Nannan

AU - Hahn, Oliver

AU - Gate, David

AU - McNerney, M. Windy

AU - Channappa, Divya

AU - Cobos, Inma

AU - Ludwig, Nicole

AU - Schulz-Schaeffer, Walter J.

AU - Keller, Andreas

AU - Wyss-Coray, Tony

N1 - Funding Information: Acknowledgements We thank N. Khoury, T. Iram, E. Tapp and other members of the laboratories of T.W.-C. and A.K. for feedback and support, and H. Zhang and K. Dickey for laboratory management. This work was funded by the NOMIS Foundation (T.W.-C.), the National Institute on Aging (T32-AG0047126 to A.C.Y. and 1RF1AG059694 to T.W.-C.), Nan Fung Life Sciences (T.W.-C.), the Bertarelli Brain Rejuvenation Sequencing Cluster (an initiative of the Stanford Wu Tsai Neurosciences Institute) and the Stanford Alzheimer’s Disease Research Center (P30 AG066515). A.C.Y. was supported by a Siebel Scholarship. F.K., G.P.S., T.F., W.J.S.-S. and A.K. are a part of the CORSAAR study supported by the State of Saarland, the Saarland University and the Rolf M. Schwiete Stiftung. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/7/22

Y1 - 2021/7/22

N2 - 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.

AB - 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.

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DO - 10.1038/s41586-021-03710-0

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EP - 571

JO - Nature

JF - Nature

IS - 7868

ER -

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

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