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COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets

Abstract

COVID-19, caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple-organ failure1–4, but little is known about its pathophysiology. Here, we generated single-cell atlases of 23 lung, 16 kidney, 16 liver and 19 heart COVID-19 autopsy donor tissue samples, and spatial atlases of 14 lung donors. Integrated computational analysis uncovered substantial remodeling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63+ intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in COVID-19 donor heart tissue, and mapped cell types and genes implicated with disease severity based on COVID-19 GWAS. Our foundational dataset elucidates the biological impact of severe SARS-CoV-2 infection across the body, a key step towards new treatments.

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Correspondence to Ioannis S. Vlachos or Alex K. Shalek or Alexandra-Chloé Villani or Orit Rozenblatt-Rosen or Aviv Regev.

Supplementary information

Supplementary Information

This file contains the Supplementary Methods and full descriptions for Supplementary Tables 1-14.

Reporting Summary

Supplementary Table 1

Clinical meta-data for all donors and extended sample information – see Supplementary Information document for full legend.

Supplementary Table 2

Studies included for building tissue meta-atlases and lung classifier coefficients – see Supplementary Information document for full legend.

Supplementary Table 3

Differentially expressed genes within KRT8+/PATS cell subsets and between the IPBLP and basal cell subsets – see Supplementary Information document for full legend.

Supplementary Table 4

Differentially expressed genes between healthy vs. COVID-19 lung (sc/snRNA-Seq) and between lung biopsies high vs. low/no viral load (bulkRNA-Seq) – see Supplementary Information document for full legend.

Supplementary Table 5

Analyses of SARS-CoV-2 RNA+ cells by cell type and viral sequencing – see Supplementary Information document for full legend.

Supplementary Table 6

Spatial assay probe list and DE genes between COVID-19 and healthy donors – see Supplementary Information document for full legend.

Supplementary Table 7

Differential expression results of snRNA-Seq based on the reconciled annotation – see Supplementary Information document for full legend.

Supplementary Table 8

Cell type markers used for cell type deconvolution of WTA and CTA data in lung spatial data – see Supplementary Information document for full legend.

Supplementary Table 9

Spatial differentially expressed genes in SARS-CoV-2 high vs. low and inflamed vs. non-inflamed – see Supplementary Information document for full legend.

Supplementary Table 10

COVID-19 heart differential expression analysis and GSEA results – see Supplementary Information document for full legend.

Supplementary Table 11

COVID-19 GWAS gene list, differential expression analysis and Sc-linker heritability results – see Supplementary Information document for full legend.

Supplementary Table 12

Gene signatures used for high-level manual annotation of COVID-19 lung cells.

Supplementary Table 13

List of differential gene expression between sub-clusters of myeloid cells, T and NK cells, B and plasma cells, and endothelial cells in COVID-19 lung, as computed by Pegasus – see Supplementary Information document for full legend.

Supplementary Table 14

List of top genes for LIGER factors of epithelial and fibroblast cells in COVID-19 lung – see Supplementary Information document for full legend.

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Delorey, T.M., Ziegler, C.G.K., Heimberg, G. et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature (2021). https://doi.org/10.1038/s41586-021-03570-8

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