COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.
Nature , 2021/07;595(7865):107-113.
Delorey TM [1 ] , Ziegler CGK [2 , 3, 4, 5, 6, 7 , Heimberg G [1 ] , Normand R [2 , 8, 9, 10, 11 , Yang Y [1 , 8 , Segerstolpe Å [1 ] , Abbondanza D [1 ] , Fleming SJ [12 , 13 , Subramanian A [1 ] , Montoro DT [2 ] , Jagadeesh KA [1 ] , Dey KK [14 ] , Sen P [2 , 8, 15, 16 , Slyper M [1 ] , Pita-Juárez YH [2 , 10, 17, 18, 19 , Phillips D [1 ] , Biermann J [20 , 21 , Bloom-Ackermann Z [22 ] , Barkas N [12 ] , Ganna A [23 , 24 , Gomez J [22 ] , Melms JC [20 , 21 , Katsyv I [25 ] , Normandin E [2 , 10 , Naderi P [10 , 17, 18 , Popov YV [10 , 26, 27 , Raju SS [2 , 28, 29 , Niezen S [10 , 26, 27 , Tsai LT [2 , 10, 26, 30, 31 , Siddle KJ [2 , 32 , Sud M [1 ] , Tran VM [22 ] , Vellarikkal SK [2 , 33 , Wang Y [20 , 21 , Amir-Zilberstein L [1 ] , Atri DS [2 , 33 , Beechem J [34 ] , Brook OR [35 ] , Chen J [2 , 36 , Divakar P [34 ] , Dorceus P [1 ] , Engreitz JM [2 , 37 , Essene A [26 , 30, 31 , Fitzgerald DM [38 ] , Fropf R [34 ] , Gazal S [39 ] , Gould J [1 , 12 , Grzyb J [40 ] , Harvey T [1 ] , Hecht J [10 , 17 , Hether T [34 ] , Jané-Valbuena J [1 ] , Leney-Greene M [2 ] , Ma H [1 , 8 , McCabe C [1 ] , McLoughlin DE [38 ] , Miller EM [34 ] , Muus C [2 , 41 , Niemi M [23 ] , Padera R [40 , 42, 43 , Pan L [34 ] , Pant D [26 , 30, 31 , Pe'er C [1 ] , Pfiffner-Borges J [1 ] , Pinto CJ [16 , 38 , Plaisted J [40 ] , Reeves J [34 ] , Ross M [34 ] , Rudy M [2 ] , Rueckert EH [34 ] , Siciliano M [40 ] , Sturm A [22 ] , Todres E [1 ] , Waghray A [44 , 45 , Warren S [34 ] , Zhang S [22 ] , Zollinger DR [34 ] , Cosimi L [46 ] , Gupta RM [2 , 33 , Hacohen N [2 , 9, 47 , Hibshoosh H [25 ] , Hide W [10 , 17, 18, 19 , Price AL [14 ] , Rajagopal J [38 ] , Tata PR [48 ] , Riedel S [10 , 17 , Szabo G [2 , 10, 26 , Tickle TL [1 , 12 , Ellinor PT [49 ] , Hung D [22 , 50, 51 , Sabeti PC [2 , 32, 52, 53, 54 , Novak R [55 ] , Rogers R [26 , 56 , Ingber DE [41 , 55, 57 , Jiang ZG [10 , 26, 27 , Juric D [16 , 38 , Babadi M [12 , 13 , Farhi SL [1 ] , Izar B [20 , 21, 58, 59 , Stone JR [36 ] , Vlachos IS [60 , 61, 62, 63, 64 , Solomon IH [40 ] , Ashenberg O [1 ] , Porter CBM [1 ] , Li B [1 , 8, 16 , Shalek AK [65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 , Villani AC [76 , 77, 78, 79 , Rozenblatt-Rosen O [80 , 81 , Regev A [82 , 83, 84, 85
Affiliations
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Program in Health Sciences & Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, USA. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Massachusetts Institute of Technology, Cambridge, MA, USA. Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA. Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. Columbia Center for Translational Immunology, New York, NY, USA. Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Institute for Molecular Medicine Finland, Helsinki, Finland. Analytical & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA. Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core Boston, Boston, MA, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. Divisions of Cardiovascular Medicine and Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. NanoString Technologies Inc, Seattle, WA, USA. Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Department of Genetics and BASE Initiative, Stanford University School of Medicine, Stanford, CA, USA. Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA. Department of Pathology, Harvard Medical School, Boston, MA, USA. Harvard Stem Cell Institute, Cambridge, MA, USA. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. Infectious Diseases Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Genetics, Harvard Medical School, Boston, MA, USA. Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. Massachusetts General Hospital, Boston, MA, USA. Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. Program for Mathematical Genomics, Columbia University Irving Medical Center, New York, NY, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. ivlachos@bidmc.harvard.edu. Harvard Medical School, Boston, MA, USA. ivlachos@bidmc.harvard.edu. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. ivlachos@bidmc.harvard.edu. Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. ivlachos@bidmc.harvard.edu. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. ivlachos@bidmc.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. shalek@mit.edu. Program in Health Sciences & Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, USA. shalek@mit.edu. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. shalek@mit.edu. Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. shalek@mit.edu. Harvard Medical School, Boston, MA, USA. shalek@mit.edu. Harvard Stem Cell Institute, Cambridge, MA, USA. shalek@mit.edu. Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu. Program in Immunology, Harvard Medical School, Boston, MA, USA. shalek@mit.edu. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. avillani@mgh.harvard.edu. Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. avillani@mgh.harvard.edu. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. avillani@mgh.harvard.edu. Department of Medicine, Harvard Medical School, Boston, MA, USA. avillani@mgh.harvard.edu. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. orit.r.rosen@gmail.com. Genentech, South San Francisco, CA, USA. orit.r.rosen@gmail.com. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Howard Hughes Medical Institute, Chevy Chase, MD, USA. aviv.regev.sc@gmail.com. Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com. PMID: 33915569 DOI: 10.1038/s41586-021-03570-8
Impact factor: 69.504
Abstract
COVID-19, which is 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 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.
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