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Cited by 620Long-Term Effects of COVID-19Single-cell and spatial transcriptomicsSARS-CoV-2 and COVID-19 Research

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

Open access
Yang, Andrew C., Kern, Fabian, Losada, Patricia M., Agam, Maayan R., Maat, Christina A., Schmartz, Georges P., Fehlmann, Tobias, Stein, Julian A. +15 more·2021·Nature
DOI 10.1038/s41586-021-03710-0PMC PMC8400927

Published version of a preprint

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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. Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

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Crossref · 10.1038/s41586-021-03710-0

Cites

109 of 109 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Choroid plexus barrier cells and brain vascular cells express several genes relevant to SARS-CoV-2 entry into the brain.

    “Similar to brain vascular cells, choroid barrier cells robustly expressed several genes that are relevant to SARS-CoV-2 brain entry”
    • Also stated in: § Brain barriers relay inflammation · plain
      “Brain and choroid cell types express several SARS-CoV-2 entry genes”
    Quote in the paperSubstantial claim
  • Findingown data

    Cell-cell communication analysis predicted a strong increase in choroid-to-cortex signaling via CCL and CXCL chemokines from choroid plexus epithelium to brain astrocytes, oligodendrocytes, microglia, and L2/3 and L4 excitatory neurons in COVID-19.

    “We observed a strong increase in the choroid-to-cortex network across key inflammatory pathways, such as the CCL and CXCL family of chemokines from the choroid plexus epithelium to brain astrocytes, oligodendrocytes, microglia and layer (L) 2/3 and L4 excitatory neurons”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Predicted ligand-receptor interactions from CellChat reflect actual intercellular signaling in the brain.
  • Findingown data

    IFITM3 is broadly upregulated across choroid and glia limitans barrier cells in patients with COVID-19.

    “We observed a broad upregulation of the antiviral defence gene IFITM3 across choroid and glia limitans barrier cells in patients with COVID-19”
    Quote in the paperSubstantial claim
  • Findingown data

    All major brain parenchymal cell types show differential gene expression in COVID-19.

    “Overall, these data demonstrate that all major brain parenchymal cell types are affected in COVID-19.”
    • Also stated in: § Cortex and choroid plexus cell types · plain
      “786 unique differentially expressed genes (DEGs) that implicated all major cell types”
    Quote in the paperSubstantial claim
  • Findingown data

    No new subpopulations were observed for oligodendrocyte lineage cells in COVID-19.

    “By contrast, we did not observe any new subpopulations for oligodendrocyte lineage cells”
    Quote in the paperNot a substantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    Some control samples without viral infection had high cycle counts between 37 and 40, which previous work without such controls interpreted as evidence of neuroinvasion.

    “Some of the samples from the control individuals without viral infection have high cycle counts (between 37 and 40), which in previous work (without such controls) has been interpreted as evidence of neuroinvasion9,18.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Matschke, J. et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 19, 919–929 (2020). source

      Not checked in the free run.

    • cites [18] Meinhardt, J. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat. Neurosci. 24, 168–175 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Cortical T cells were detected in all but one COVID-19 patient and in none of the control samples.

    “although we did not find cortical T cells in any of our samples from control individuals (without viral infection or with terminal influenza), we detected them in all but one of the patients with COVID-19”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The COVID-19-associated microglial subpopulation is marked by expression of activation genes such as C1QC, CD74, FTL and FTH1, and by downregulation of homeostatic markers including P2RY12.

    “This subpopulation was marked by expression of microglial activation genes previously associated with human disease4,5, such as complement C1QC, CD74, FTL and FTH1, and downregulation of the homeostatic markers including P2RY12”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

    • cites [5] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The study generated 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples, comprising 14 control individuals (including one terminal influenza case) and 8 COVID-19 patients.

    “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.”
    • Also stated in: § Abstract · plain
      “Here we characterized the transcriptomes of 65,309 nuclei isolated from the brains of 14 control individuals and 8 patients with COVID-19”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neuronal perturbations in COVID-19 were unique compared with chronic CNS diseases, while the overlap in glial cells was particularly strong.

    “Although neuronal perturbations in COVID-19 were unique compared to those in chronic CNS diseases, the overlap in glial cells was particularly strong”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In COVID-19, synaptic genes mediating neurotransmission such as VAMP2, SNAP25 and ATP6V0C are downregulated in L2/3 excitatory neurons, while proximal VIP inhibitory neurons show concomitant upregulation.

    “Specifically, the downregulation of synaptic genes that mediate neurotransmission (for example, VAMP2, SNAP25 and ATP6V0C) in L2/3 excitatory neurons alongside a concomitant upregulation in proximal VIP inhibitory neurons”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unsupervised clustering of nuclear transcriptomes yielded 14 cell types, including excitatory neuron and interneuron subtypes that express established marker genes.

    “Our unsupervised clustering of nuclear transcriptomes yielded 14 cell types, including subtypes of excitatory neurons and interneurons that express previously established marker genes”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A COVID-19-enriched OPC subcluster shows a trend that is not statistically significant.

    “UMAP projection of OPCs and trending but not significant emergence of a COVID-19-enriched subcluster.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The count of nuclei per cell type and the count of predicted DEGs show no significant correlation (Pearson, not significant).

    “Comparison of the number of nuclei isolated per cell type and the number of predicted DEGs. Two-sided P-value indicates the significance of the correlation (Pearson, not significant).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In COVID-19 astrocytes, inflammatory genes are upregulated and homeostatic genes are dysregulated.

    “Example upregulation of inflammatory and dysregulation of homeostatic genes in COVID-19 astrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Dounce homogenization or enzymatic dissociation of choroid plexus resulted in loss of nuclei integrity and low nuclei complexity.

    “Dounce homogenization or enzymatic dissociation resulted in loss of nuclei integrity and low nuclei complexity (<50 median genes per nuclei).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    For mature oligodendrocytes, the control and COVID-19 groups do not differ significantly (P = 0.9591).

    “As in d, e, respectively, but for mature oligodendrocytes with P = 0.9591.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The proportion of OPCs in the COVID-19-enriched subcluster does not differ significantly between groups (P = 0.083).

    “Quantification of the frequency of the COVID-19-enriched OPC subcluster as a proportion of all OPCs (n = 8 control, including 1 influenza and n = 8 COVID-19, two-sided Mann–Whitney t-test, P = 0.083; mean ± s.e.m., not significant).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    No statistical methods were used to predetermine sample size, and the experiments were not randomized or blinded.

    “No statistical methods were used to predetermine sample size. The experiments were not randomized, and investigators were not blinded to allocation during experiments and outcome assessment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Control and COVID-19 samples were matched for tissue dissection area, tissue quality and RNA quality.

    “The samples in the control and COVID-19 groups were from individuals between 55 and 91 years of age and matched for tissue dissection area, tissue and RNA quality”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study's sample sizes were similar to or greater than those in previous COVID-19 or brain snRNA-seq studies.

    “Our sample sizes were similar to or greater than those reported in previous COVID-19 or brain single-nucleus RNA-sequencing (snRNA-seq) studies24-26.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018). source

      Not checked in the free run.

    • cites [25] Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019). source

      Not checked in the free run.

    • cites [26] Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aberrant T cell infiltration into the mouse brain is sufficient to promote neuroinflammation and impair neurogenesis.

    “Aberrant T cell infiltration into the mouse brain has previously been reported to be sufficient to promote neuroinflammation and impair neurogenesis35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The MRC1+ cell population did not form separate clusters in unsupervised clustering of the larger immune population and was not associated with better or lower library quality scores.

    “The MRC1+ cell population did not form separate clusters in an unsupervised clustering of the larger immune population and was not associated with better or lower library quality scores”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Library quality was not affected when analyses were restricted to the MRC1− subset of microglia.

    “Library quality was not affected upon restricting analyses to the MRC1− subset of microglia”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Excessive complement signaling in microglia is linked to premature neuronal synapse pruning in neurodegenerative disease.

    “Excessive complement signalling in microglia has previously been linked to premature neuronal synapse pruning in neurodegenerative disease33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The microglial subpopulation enriched in COVID-19 patients represents a distinct state that shares features with, but differs from, microglial states previously reported in human neurodegenerative disease.

    “Our observations suggest that the microglial subpopulation enriched in patients with COVID-19 represents a distinct microglial state that shares features with–but is ultimately different from–microglial cell states that have previously been reported in human neurodegenerative disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Sex was balanced by group, mitigating variance due to sex.

    “we balanced genders by group, mitigating variance due to sex”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The inflamed choroid plexus sends inflammatory signals into the brain, activating parenchymal glia and impairing cognitive function.

    “The inflamed choroid plexus has previously been shown to send inflammatory signals into the brain, thereby activating parenchymal glia and impairing cognitive function31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The immunohistochemical staining results were reproduced in at least two separate experiments.

    “Immunohistochemical stains are representative of at least two independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An earlier study divided PMI-sensitive genes into two groups: upregulated glial genes and downregulated neural genes.

    “The previous study27 categorized PMI-sensitive genes in two categories: glial genes upregulated and neural genes downregulated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Dachet, F. et al. Selective time-dependent changes in activity and cell-specific gene expression in human postmortem brain. Sci. Rep. 11, 6078 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A pattern of synaptic dysfunction in upper-layer cortical circuitry has previously been reported in autism and correlated with cognitive deficits.

    “Such a pattern of dysfunction has previously been reported in an snRNA-seq study of autism and correlated with cognitive deficits8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Velmeshev, D. et al. Single-cell genomics identifies cell type-specific molecular changes in autism. Science 364, 685–689 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    PMI-sensitive genes are not among the COVID-19 DEGs and therefore do not drive the DEG-based findings.

    “Heat map showing that PMI-sensitive genes are not the DEGs in COVID-19 and thus not driving the DEG-based findings of our study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High-quality fresh-frozen human brain tissue from COVID-19 patients needed for single-cell transcriptomic studies is largely inaccessible, and methods to isolate human brain barrier cells have only recently emerged.

    “This is in part because the high-quality, fresh-frozen human brain tissue from patients with COVID-19 needed for single-cell transcriptomic studies is largely inaccessible, and methods to isolate human brain barrier cells have only recently emerged22,23.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Dani, N. et al. A cellular and spatial map of the choroid plexus across brain ventricles and ages. Cell 184, 3056–3074 (2021). source

      Not checked in the free run.

    • cites [23] Yang, A. C. et al. A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk. Preprint at https://doi.org/10.1101/2021.04.26.441262 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    A comprehensive assessment across specific cell types in the brain affected by severe COVID-19 is missing.

    “Critically, a comprehensive assessment across specific cell types in the brain affected by severe COVID-19 is missing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A smaller background set of 17,926 protein-coding genes leaves the qualitative statistical significance of the overlaps unchanged.

    “Using the smaller set of 17,926 protein-coding genes as background does not change the qualitative statistical significance of the overlaps.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent reports have found SARS-CoV-2 infection of cultured choroid plexus organoids.

    “Recent reports have found SARS-CoV-2 infection of cultured choroid plexus organoids20,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Jacob, F. et al. Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell 27, 937–950 (2020). source

      Not checked in the free run.

    • cites [21] Pellegrini, L. et al. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell 27, 951–961 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study obtained approval from local ethics committees for the use of post-mortem tissue.

    “with approval from local ethics committees”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    No statistical method was used to predetermine sample sizes, but the sample sizes resemble those in earlier publications.

    “We did not use statistical methods to predetermine sample sizes, but they are similar to those reported in previous publications24,25,49.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70–80 (2018). source

      Not checked in the free run.

    • cites [25] Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019). source

      Not checked in the free run.

    • cites [49] Zhong, S. et al. A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex. Nature 555, 524–528 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IFITM3 serves as the first line of defence against viral infection, and its upregulation is a marker of SARS-CoV-2 infection across public datasets.

    “IFITM3 serves as the first line of defence against viral infection28 and its upregulation is a marker of SARS-CoV-2 infection across public datasets29.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Bailey, C. C., Zhong, G., Huang, I. C. & Farzan, M. IFITM-family proteins: the cell’s first line of antiviral defense. Annu. Rev. Virol. 1, 261–283 (2014). source

      Not checked in the free run.

    • cites [29] Hachim, M. Y. et al. Interferon-induced transmembrane protein (IFITM3) is upregulated explicitly in SARS-CoV-2 infected lung epithelial cells. Front. Immunol. 11, 1372 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sex and batch were set as latent variables in the differential expression analysis.

    “Sex and batch were set as latent variables.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Microglial subclusters associated with disease have been identified for various neurodegenerative diseases.

    “Microglial subclusters that are associated with disease have been identified for various neurodegenerative diseases4,5.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). source

      Not checked in the free run.

    • cites [5] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neuropathology may arise from direct virus neuroinvasion or indirectly from peripheral infection and its attendant immune response.

    “Neuropathology may arise from direct virus neuroinvasion or indirectly from peripheral infection and its attendant immune response16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Iadecola, C., Anrather, J. & Kamel, H. Effects of COVID-19 on the nervous system. Cell 183, 16–27 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is a precedent for acute viral infections causing long-term inflammation and dysfunction that predisposes individuals to neurodegenerative disease.

    “There is a precedent for acute viral infections causing long-term inflammation and dysfunction that predisposes individuals to neurodegenerative disease44,45”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Hosseini, S. et al. Long-term neuroinflammation induced by influenza a virus infection and the impact on hippocampal neuron morphology and function. J. Neurosci. 38, 3060–3080 (2018). source

      Not checked in the free run.

    • cites [45] Deleidi, M. & Isacson, O. Viral and inflammatory triggers of neurodegenerative diseases. Sci. Transl. Med. 4, 121ps3 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    L2/3 excitatory neurons are cortico-cortical projecting and exhibit sparse action potential firing to generate a simple and reliable neural code for associative learning.

    “L2/3 excitatory neurons are cortico-cortical projecting and already exhibit sparse action potential firing to generate a simple and reliable neural code for associative learning41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Petersen, C. C. H. & Crochet, S. Synaptic computation and sensory processing in neocortical layer 2/3. Neuron 78, 28–48 (2013). source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    Predicted ligand-receptor interactions from CellChat reflect actual intercellular signaling in the brain.

    “Cell–cell interactions based on the expression of known ligand–receptor pairs in different cell types were inferred using CellChat32”

  • The paper relies on this without support.

    Transcriptional differences between COVID-19 and control samples are attributable to COVID-19 rather than to differences in critical illness, mechanical ventilation, or other pre-mortem factors not fully controlled.

    “The cause of death for nearly all patients with COVID-19 or influenza was interstitial pneumonia after more than two weeks of mechanical ventilation.”
2 of 2

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  • CellChat is cited with two different reference numbers

    Minor

    The Extended Data caption cites CellChat as reference 34, while the Methods cite it as reference 32. Reference 34 is a different work in the paper's reference list.

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Authors
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., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., & Wyss-Coray, T.
Affiliations
  • Stanford Medicine (US)
  • Saarland University (DE)
  • Universitätsklinikum des Saarlandes (DE)
Corresponding author
Keller, Andreas
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-06-21
Volume
595
Issue
7868
Pages
565-571
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03710-0
PMC
PMC8400927
OpenAlex
W3175961346
Semantic Scholar
03d2ecf9b2edd606d5e97b86188fd11d4139b15e
Cited by
620
References
109
Citations by year
2026: 50 · 2025: 59 · 2024: 111 · 2023: 138 · 2022: 166 · 2021: 95 · 2020: 1
FWCI
61.00
Type
journal article
Language
en
Update notices
correction (2021-10-08)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Universität des Saarlandes
  • NOMIS Stiftung
  • Wu Tsai Neurosciences Institute, Stanford University
  • National Institute on Aging (T32AG0047126, AG0047126, AG066515, RF1AG059694, T32AG047126, P30AG066515)
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
COVID-19 pandemic, SARS-CoV-2, neuroinflammation, choroid plexus, frontal cortex, single-nucleus transcriptomics, microglia, astrocytes, T cell infiltration, peripheral inflammation, excitatory neurons, synaptic signalling, neurodegenerative diseases, schizophrenia, depression, cognitive function, brain cell types
MeSH terms
COVID-19, SARS-CoV-2, Aged, Aged, 80 and over, Astrocytes, Brain, Cell Nucleus, Choroid Plexus, Female, Humans, Inflammation, Male, Middle Aged, Neurons, Virus Replication, Microglia, Single-Cell Analysis, Transcriptome

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