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
Abstract
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1,2,3. 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 disease4,5,6. 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.
Datasets
1. A total of 38,217 droplet-based single-nucleus transcriptomes profiled across 14 cell types in the frontal cortex
Metadata
Sample
Brain.region
Prep
Cause_of_death_comorbidities
Biogroup
author_disease
Batch
integrated_snn_res.0.2
seurat_clusters
integrated_snn_res.0.3
integrated_snn_res.3
integrated_snn_res.1
integrated_snn_res.5
integrated_snn_res.0.5
cellID
cellID2
assay_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
self_reported_ethnicity_ontology_term_id
organism_ontology_term_id
sex_ontology_term_id
tissue_ontology_term_id
donor_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
Medial frontal cortex38217 cells Interstitial pneumonia, multiorgan failure; arterial hypertonia, diabetes type II without insulin supplementation5118 cells Superinfected interstitial pneumonia; smoker of 25-30 pack years until 15 years before death, depression, clipped cerebral aneurysm3348 cells Interstitial pneumonia, hypovolemic shock; arterial hypertonia, atrial fibrillation, pulmonary emphysema with barrel chest3229 cells Tongue cancer, metastasis to the neck and lung2992 cells Superinfected interstitial pneumonia, severe arterosclerosis with dilatative heart disease; arterial hypertonia, hyperlipidemia, diabetes type II with insulin supplementation, coronary heart disease, cerebral insult (occlusion of the A. carotis communis; mechanical recanalisation with A. carotis stent and lysis therapy) in 20142872 cells Superinfected interstitial pneumonia, unexpected sudden death in the hospital; Asthma bronchiale, arterial hypertonia2582 cells Hypovolemic shock because of aneurysma dissecans of the aorta and acute rupture of the aneurysm; arterial hypertonia, systemic vasculitis, immunosuppressive glucocorticoid-therapy2426 cells Breast cancer; diabetes type II2188 cells Myocardial infarction; diabetes type II, hypertension, end-stage renal disease2055 cells Superinfected interstitial pneumonia, multiorgan failure; coronary heart disease, cardiomyopathy, atrial fibrillation, nicotine and alcohol abuse2049 cells End stage heart disease; diabetes type II, hypertension, hypercholesterolemia1957 cells Small cell lung cancer; diabetes type II, coronary artery disease, COPD1897 cells COPD w/ interstitial lung disease & emphysema; rheumatoid arthritis, congestive heart failure, hypothyroidism, transfusion-dependent MDS1523 cells Superinfected interstitial pneumonia; arterial hypertonia, anemia perniciosa, rheumatoid polyarthritis1458 cells Coronary artery disease, endstage cardiomyopathy; diabetes type II 1285 cells Interstitial pneumonia, dilated heart disease; arterial hypertonia, atrial fibrillation, pulmonary emphysema with barrel chest1238 cells Excitatory neuron10589 cells Oligodendrocyte10259 cells Inhibitory neuron4768 cells Oligodendrocyte10259 cells L2/3 excitatory neuron5425 cells L4 excitatory neuron3978 cells VIP interneuron1964 cells L5/6 CC excitatory neuron669 cells SV2C interneuron595 cells L5/6 excitatory neuron517 cells HANCESTRO:000538217 cells NCBITaxon:960638217 cells UBERON:002235238217 cells oligodendrocyte10259 cells L2/3 intratelencephalic projecting glutamatergic neuron5425 cells L4 intratelencephalic projecting glutamatergic neuron3978 cells oligodendrocyte precursor cell2671 cells cerebral cortex neuron2060 cells vip GABAergic cortical interneuron1964 cells microglial cell1949 cells pvalb GABAergic cortical interneuron1274 cells L5/6 near-projecting glutamatergic neuron1186 cells sst GABAergic cortical interneuron935 cells cerebral cortex GABAergic interneuron595 cells endothelial cell289 cells myocardial infarction2055 cells small cell lung carcinoma1897 cells chronic obstructive pulmonary disease1523 cells medial orbital frontal cortex38217 cells 55-year-old human stage5118 cells 79-year-old human stage5060 cells 69-year-old human stage3664 cells 60-year-old human stage3348 cells 57-year-old human stage3229 cells 83-year-old human stage2992 cells 78-year-old human stage2582 cells 63-year-old human stage2055 cells 66-year-old human stage2049 cells 90-year-old human stage1957 cells 77-year-old human stage1897 cells 82-year-old human stage1523 cells 68-year-old human stage1458 cells 58-year-old human stage1285 cells 2. A total of 27,092 droplet-based single-nucleus transcriptomes profiled across 11 cell types in the choroid plexus
Metadata
Sample
Brain.region
Prep
Cause_of_death_comorbidities
Biogroup
author_disease
Batch
integrated_snn_res.0.2
seurat_clusters
integrated_snn_res.0.3
cellID2
cellID
integrated_snn_res.0.5
assay_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
self_reported_ethnicity_ontology_term_id
organism_ontology_term_id
sex_ontology_term_id
tissue_ontology_term_id
donor_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
Choroid plexus27092 cells Lateral ventricles27092 cells Aspiration pneumonia & Frontotemporal lobar degeneration 5809 cells Aspiration pneumonia & Alzheimer's disease3797 cells Superinfected interstitial pneumonia; smoker of 25-30 pack years until 15 years before death, depression, clipped cerebral aneurysm3656 cells Interstitial pneumonia, multiorgan failure; arterial hypertonia, diabetes type II without insulin supplementation3028 cells Superinfected interstitial pneumonia, multiorgan failure; coronary heart disease, cardiomyopathy, atrial fibrillation, nicotine and alcohol abuse2748 cells Pancreatic cancer & Parkinson’s disease2148 cells Hypovolemic shock because of aneurysma dissecans of the aorta and acute rupture of the aneurysm; arterial hypertonia, systemic vasculitis, immunosuppressive glucocorticoid-therapy1476 cells Interstitial pneumonia, hypovolemic shock; arterial hypertonia, atrial fibrillation, pulmonary emphysema with barrel chest1401 cells Superinfected interstitial pneumonia; arterial hypertonia, anemia perniciosa, rheumatoid polyarthritis1216 cells Superinfected interstitial pneumonia, severe arterosclerosis with dilatative heart disease; arterial hypertonia, hyperlipidemia, diabetes type II with insulin supplementation, coronary heart disease, cerebral insult (occlusion of the A. carotis communis; mechanical recanalisation with A. carotis stent and lysis therapy) in 20141052 cells Aspiration pneumonia & Multiple system atrophy598 cells Interstitial pneumonia, dilated heart disease; arterial hypertonia, atrial fibrillation, pulmonary emphysema with barrel chest163 cells MT-hi Epithelial3345 cells GPX3-hi Epithelial1662 cells SLC26A3-hi Epithelial1434 cells PRLR-hi Epithelial750 cells HANCESTRO:000527092 cells NCBITaxon:960627092 cells UBERON:000188627092 cells choroid plexus epithelial cell21198 cells mesenchymal cell3208 cells cerebral cortex endothelial cell145 cells aspiration pneumonia10204 cells malignant pancreatic neoplasm2148 cells choroid plexus27092 cells 74-year-old human stage3750 cells 60-year-old human stage3656 cells 78-year-old human stage3345 cells 55-year-old human stage3028 cells 66-year-old human stage2748 cells 84-year-old human stage2148 cells 85-year-old human stage2059 cells 69-year-old human stage1639 cells 57-year-old human stage1401 cells 68-year-old human stage1216 cells 79-year-old human stage1052 cells 71-year-old human stage598 cells 91-year-old human stage452 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/59c9ecfe-c47d-4a6a-bab0-895cc0c1942b
Alias names
GSE159812, PMID34153974, PMC8400927
Cite this study
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. and Calcuttawala, K., 2021. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 595(7868), pp.565-571. https://doi.org/10.1038/s41586-021-03710-0
