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

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure 1 – 4 , but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases o...

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Published inNature (London) Vol. 595; no. 7865; pp. 107 - 113
Main Authors Ziegler, Carly G. K., Heimberg, Graham, Normand, Rachelly, Yang, Yiming, Segerstolpe, Åsa, Abbondanza, Domenic, Fleming, Stephen J., Montoro, Daniel T., Jagadeesh, Karthik A., Dey, Kushal K., Sen, Pritha, Slyper, Michal, Pita-Juárez, Yered H., Phillips, Devan, Biermann, Jana, Bloom-Ackermann, Zohar, Barkas, Nikolaos, Ganna, Andrea, Gomez, James, Melms, Johannes C., Katsyv, Igor, Normandin, Erica, Naderi, Pourya, Popov, Yury V., Raju, Siddharth S., Niezen, Sebastian, Tsai, Linus T.-Y., Siddle, Katherine J., Sud, Malika, Tran, Victoria M., Vellarikkal, Shamsudheen K., Wang, Yiping, Amir-Zilberstein, Liat, Atri, Deepak S., Beechem, Joseph, Brook, Olga R., Chen, Jonathan, Divakar, Prajan, Engreitz, Jesse M., Essene, Adam, Fitzgerald, Donna M., Fropf, Robin, Gazal, Steven, Gould, Joshua, Grzyb, John, Harvey, Tyler, Hether, Tyler, Jané-Valbuena, Judit, Leney-Greene, Michael, Ma, Hui, McCabe, Cristin, McLoughlin, Daniel E., Miller, Eric M., Muus, Christoph, Niemi, Mari, Padera, Robert, Pan, Liuliu, Pant, Deepti, Pe’er, Carmel, Pfiffner-Borges, Jenna, Pinto, Christopher J., Plaisted, Jacob, Reeves, Jason, Ross, Marty, Rudy, Melissa, Rueckert, Erroll H., Siciliano, Michelle, Sturm, Alexander, Waghray, Avinash, Warren, Sarah, Zhang, Shuting, Zollinger, Daniel R., Cosimi, Lisa, Gupta, Rajat M., Hacohen, Nir, Hibshoosh, Hanina, Hide, Winston, Price, Alkes L., Rajagopal, Jayaraj, Tata, Purushothama Rao, Riedel, Stefan, Szabo, Gyongyi, Tickle, Timothy L., Hung, Deborah, Sabeti, Pardis C., Novak, Richard, Rogers, Robert, Ingber, Donald E., Jiang, Z. Gordon, Juric, Dejan, Izar, Benjamin, Stone, James R., Vlachos, Ioannis S., Solomon, Isaac H., Ashenberg, Orr, Porter, Caroline B. M., Li, Bo, Shalek, Alex K., Villani, Alexandra-Chloé, Regev, Aviv
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.07.2021
Nature Publishing Group
Subjects
38
45/91
631/208
631/250/255/2514
631/326/596/4130
Adult
Aged
Aged, 80 and over
Alveoli
Annotations
Atlases as Topic
Autopsies
Autopsy
Biobanks
Biological effects
Biological Specimen Banks
Cells (biology)
Computer applications
Coronaviruses
COVID-19
COVID-19 - genetics
COVID-19 - immunology
COVID-19 - pathology
COVID-19 - virology
Endothelial Cells
Epithelial Cells - pathology
Epithelial Cells - virology
Female
Fibroblasts
Genome-wide association studies
Genome-Wide Association Study
Genomes
Heart
Heart - virology
Humanities and Social Sciences
Humans
Infections
Inflammation
Inflammation - pathology
Inflammation - virology
Kidney - pathology
Kidney - virology
Liver
Liver - pathology
Liver - virology
Lung - pathology
Lung - virology
Lungs
Male
Middle Aged
multidisciplinary
Myocardium - pathology
Organ Specificity
Pathophysiology
Phagocytes
Progenitor cells
Pulmonary Alveoli - pathology
Pulmonary Alveoli - virology
Regeneration
Respiratory distress syndrome
RNA, Viral - analysis
SARS-CoV-2 - immunology
SARS-CoV-2 - pathogenicity
Science
Science (multidisciplinary)
Severe acute respiratory syndrome coronavirus 2
Single-Cell Analysis
Spatial analysis
Stem cells
Tissue engineering
Tissues
Transcription
Viral diseases
Viral Load
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Summary:COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure 1 – 4 , but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling 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 heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments. Single-cell analysis of lung, heart, kidney and liver autopsy samples shows the molecular and cellular changes and immune response resulting from severe COVID-19 infection.
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these authors jointly supervised this work
Author Contributions
A.K.S., A.C.V., I.S.V., Z.G.J, O.R.-R., and A.R. conceived and led the study. These authors contributed equally as co-second authors: Z.B.-A., N.B., A.G., J.G., J.C.M., I.K., E.N., P.N., Y.V.P., S.S.R., S.N., L.T.-Y.T., K.J.S., M.Su., V.M.T., S.K.V., Y.W. T.M.D., C.G.K.Z., Å. S, D.A. designed protocols and carried out experiments together with D.P., Z.B.-A., V.M.T., A.S, S.Z., J.G., J.H., E.N., M.Su, C.M, L.T., A.E., D.Pa., L.P., JC.M, L.A.-Z. C.B.M.P., C.G.K.Z., O.A., R.N., G.H., K.J., K.S., B.L., Y.Y., S.F., A.S., P.N., Y.P.J., P.N., T.He., J.R., W.H., I.S.V., T.M.D and J.B. designed and performed computational analysis. M.B., N.B., J.G., Y.W., R.G., S.S.R., H.M., P.S, A.W., C.M., M. L.-G., T.H., D.T.M., S.W., D.R.Z., E.R., M.R, E.M., R.F., P.Di., A.G., C.Pe. and M.N. provided input to and assisted with computational analysis. K.J., K.D., A.G., J.E., S.G., A.R. and A.P., contributed methods and performed integrated analysis for GWAS. P.R.T., D.T.M., Z.G.J., Y.P., G.S., S.N., S.R., and J.R. provided clinical and biological expertise. D.F., D.J., D.E.M, C.P., S.K.V., E.K. and J.S. provided clinical expertise, performed sample acquisition and/or administrative coordination at MGH. J.H., R.R, R.N., O.R.B., Z.G.J., Y.P., and D.I. provided clinical expertise, performed sample acquisition and/or administrative coordination at BIDMC. I.H.S., D.A., L.C., J.G., R.P., M.Si., provided clinical expertise, performed sample acquisition and/or administrative coordination at BWH. I.G., H.H., B.I. provided clinical expertise, performed sample acquisition and/or administrative coordination at CUIMC/NYP. P.D., D.P., J.J-V., and J.B. helped with sample coordination and sample receipt at the Broad Institute. N.B and S.R. performed bulk RNA-Seq deconvolution analysis. E.N., M.R and K.S. performed viral qPCR, whole genome sequencing and phylogenetic analyses. M.S. provided input for sc/snRNA-Seq experiments and protocols. J.J.-V., E.T., O.R.R., and A.C.V. managed the study and tissue acquisition. T.L.T. contributed computational expertise and advice. T.M.D., C.B.M.P., C.G.K.Z., G.H., R.N., K.J., O.A., B.L., Z.G.J., I.S.V, Y.Y., S.F., A.S., D.T.M., A.K.S., A.C.V., O.R.-R. and A. Regev wrote the manuscript, with input from all authors. D.H., P.C.S., N.H., P.T.E. supervised research.
these authors contributed equally
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-021-03570-8