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Nature
07, 2021;595 (7865): 107-113.

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

Toni M Delorey, Carly G K Ziegler, Graham Heimberg, Rachelly Normand, Yiming Yang, Åsa Segerstolpe, Domenic Abbondanza, Stephen J Fleming, Ayshwarya Subramanian, Daniel T Montoro, Karthik A Jagadeesh, Kushal K Dey, Pritha Sen, Michal Slyper, Yered H Pita-Juárez, Devan Phillips, Jana Biermann, Zohar Bloom-Ackermann, Nikolaos Barkas, Andrea Ganna, James Gomez, Johannes C Melms, Igor Katsyv, Erica Normandin, Pourya Naderi, Yury V Popov, Siddharth S Raju, Sebastian Niezen, Linus T-Y Tsai, Katherine J Siddle, Malika Sud, Victoria M Tran, Shamsudheen K Vellarikkal, Yiping Wang, Liat Amir-Zilberstein, Deepak S Atri, Joseph Beechem, Olga R Brook, Jonathan Chen, Prajan Divakar, Phylicia Dorceus, Jesse M Engreitz, Adam Essene, Donna M Fitzgerald, Robin Fropf, Steven Gazal, Joshua Gould, John Grzyb, Tyler Harvey, Jonathan Hecht, Tyler Hether, Judit Jané-Valbuena, Michael Leney-Greene, Hui Ma, Cristin McCabe, Daniel E McLoughlin, Eric M Miller, Christoph Muus, Mari Niemi, Robert Padera, Liuliu Pan, Deepti Pant, Carmel Pe'er, Jenna Pfiffner-Borges, Christopher J Pinto, Jacob Plaisted, Jason Reeves, Marty Ross, Melissa Rudy, Erroll H Rueckert, Michelle Siciliano, Alexander Sturm, Ellen Todres, Avinash Waghray, Sarah Warren, Shuting Zhang, Daniel R Zollinger, Lisa Cosimi, Rajat M Gupta, Nir Hacohen, Hanina Hibshoosh, Winston Hide, Alkes L Price, Jayaraj Rajagopal, Purushothama Rao Tata, Stefan Riedel, Gyongyi Szabo, Timothy L Tickle, Patrick T Ellinor, Deborah Hung, Pardis C Sabeti, Richard Novak, Robert Rogers, Donald E Ingber, Z Gordon Jiang, Dejan Juric, Mehrtash Babadi, Samouil L Farhi, Benjamin Izar, James R Stone, Ioannis S Vlachos, Isaac H Solomon, Orr Ashenberg, Caroline B M Porter, Bo Li, Alex K Shalek, Alexandra-Chloé Villani, Orit Rozenblatt-Rosen, Aviv Regev
Author Information
  1. Toni M Delorey: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  2. Carly G K Ziegler: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  3. Graham Heimberg: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  4. Rachelly Normand: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  5. Yiming Yang: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  6. Åsa Segerstolpe: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  7. Domenic Abbondanza: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  8. Stephen J Fleming: Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  9. Ayshwarya Subramanian: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  10. Daniel T Montoro: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  11. Karthik A Jagadeesh: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  12. Kushal K Dey: Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  13. Pritha Sen: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  14. Michal Slyper: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  15. Yered H Pita-Juárez: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  16. Devan Phillips: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  17. Jana Biermann: Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. ORCID
  18. Zohar Bloom-Ackermann: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  19. Nikolaos Barkas: Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  20. Andrea Ganna: Institute for Molecular Medicine Finland, Helsinki, Finland.
  21. James Gomez: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  22. Johannes C Melms: Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. ORCID
  23. Igor Katsyv: Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  24. Erica Normandin: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  25. Pourya Naderi: Harvard Medical School, Boston, MA, USA.
  26. Yury V Popov: Harvard Medical School, Boston, MA, USA.
  27. Siddharth S Raju: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  28. Sebastian Niezen: Harvard Medical School, Boston, MA, USA. ORCID
  29. Linus T-Y Tsai: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  30. Katherine J Siddle: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  31. Malika Sud: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  32. Victoria M Tran: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  33. Shamsudheen K Vellarikkal: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  34. Yiping Wang: Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA.
  35. Liat Amir-Zilberstein: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  36. Deepak S Atri: Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  37. Joseph Beechem: NanoString Technologies Inc, Seattle, WA, USA.
  38. Olga R Brook: Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA. ORCID
  39. Jonathan Chen: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  40. Prajan Divakar: NanoString Technologies Inc, Seattle, WA, USA.
  41. Phylicia Dorceus: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  42. Jesse M Engreitz: Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  43. Adam Essene: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  44. Donna M Fitzgerald: Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  45. Robin Fropf: NanoString Technologies Inc, Seattle, WA, USA.
  46. Steven Gazal: Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  47. Joshua Gould: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  48. John Grzyb: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  49. Tyler Harvey: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  50. Jonathan Hecht: Harvard Medical School, Boston, MA, USA.
  51. Tyler Hether: NanoString Technologies Inc, Seattle, WA, USA.
  52. Judit Jané-Valbuena: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  53. Michael Leney-Greene: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  54. Hui Ma: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  55. Cristin McCabe: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  56. Daniel E McLoughlin: Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  57. Eric M Miller: NanoString Technologies Inc, Seattle, WA, USA. ORCID
  58. Christoph Muus: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  59. Mari Niemi: Institute for Molecular Medicine Finland, Helsinki, Finland.
  60. Robert Padera: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  61. Liuliu Pan: NanoString Technologies Inc, Seattle, WA, USA.
  62. Deepti Pant: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  63. Carmel Pe'er: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  64. Jenna Pfiffner-Borges: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  65. Christopher J Pinto: Department of Medicine, Harvard Medical School, Boston, MA, USA.
  66. Jacob Plaisted: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  67. Jason Reeves: NanoString Technologies Inc, Seattle, WA, USA.
  68. Marty Ross: NanoString Technologies Inc, Seattle, WA, USA.
  69. Melissa Rudy: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  70. Erroll H Rueckert: NanoString Technologies Inc, Seattle, WA, USA.
  71. Michelle Siciliano: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  72. Alexander Sturm: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  73. Ellen Todres: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  74. Avinash Waghray: Harvard Stem Cell Institute, Cambridge, MA, USA.
  75. Sarah Warren: NanoString Technologies Inc, Seattle, WA, USA.
  76. Shuting Zhang: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  77. Daniel R Zollinger: NanoString Technologies Inc, Seattle, WA, USA.
  78. Lisa Cosimi: Infectious Diseases Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  79. Rajat M Gupta: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  80. Nir Hacohen: Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  81. Hanina Hibshoosh: Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  82. Winston Hide: Harvard Medical School, Boston, MA, USA.
  83. Alkes L Price: Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA. ORCID
  84. Jayaraj Rajagopal: Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  85. Purushothama Rao Tata: Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. ORCID
  86. Stefan Riedel: Harvard Medical School, Boston, MA, USA. ORCID
  87. Gyongyi Szabo: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  88. Timothy L Tickle: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  89. Patrick T Ellinor: Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  90. Deborah Hung: Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  91. Pardis C Sabeti: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  92. Richard Novak: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. ORCID
  93. Robert Rogers: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  94. Donald E Ingber: John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. ORCID
  95. Z Gordon Jiang: Harvard Medical School, Boston, MA, USA.
  96. Dejan Juric: Department of Medicine, Harvard Medical School, Boston, MA, USA. ORCID
  97. Mehrtash Babadi: Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  98. Samouil L Farhi: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  99. Benjamin Izar: Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. ORCID
  100. James R Stone: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  101. Ioannis S Vlachos: Broad Institute of MIT and Harvard, Cambridge, MA, USA. ivlachos@bidmc.harvard.edu. ORCID
  102. Isaac H Solomon: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. ORCID
  103. Orr Ashenberg: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  104. Caroline B M Porter: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  105. Bo Li: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  106. Alex K Shalek: Broad Institute of MIT and Harvard, Cambridge, MA, USA. shalek@mit.edu. ORCID
  107. Alexandra-Chloé Villani: Broad Institute of MIT and Harvard, Cambridge, MA, USA. avillani@mgh.harvard.edu. ORCID
  108. Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. orit.r.rosen@gmail.com. ORCID
  109. Aviv Regev: Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aviv.regev.sc@gmail.com. ORCID
PMID: 33915569 DOI: 10.1038/s41586-021-03570-8

Abstract

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure, 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.

References

  1. Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). [PMID: 32109013]
  2. Puelles, V. G. et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592 (2020). [PMID: 32402155]
  3. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020). [PMID: 31986264]
  4. Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020). [PMID: 32085846]
  5. Varga, Z. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418 (2020). [PMID: 32325026]
  6. Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 130, 2620–2629 (2020). [PMID: 32217835]
  7. Qin, C. et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 71, 762–768 (2020). [PMID: 32161940]
  8. Hadjadj, J. et al. Impaired type I interferon activity and exacerbated inflammatory responses in severe COVID-19 patients. Science 369, 718–724 (2020).
  9. Bian, X.-W. et al. Autopsy of COVID-19 patients in China. Natl. Sci. Rev. 7, 1414–1418 (2020). [>PMCID: ]
  10. Menter, T. et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 77, 198–209 (2020). [PMID: 32364264]
  11. Wichmann, D. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann. Intern. Med. 173, 268–277 (2020). [PMID: 32374815]
  12. Bösmüller, H. et al. The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation. Virchows Arch. 477, 349–357 (2020). [PMID: 32607684]
  13. Slyper, M. et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat. Med. 26, 792 –802 (2020). [PMID: 32405060]
  14. Fleming, S. J., Marioni, J. C. & Babadi, M. CellBender remove-background: a deep generative model for unsupervised removal of background noise from scRNA-seq datasets. Preprint at https://doi.org/10.1101/791699 (2019).
  15. Li, B. et al. Cumulus provides cloud-based data analysis for large-scale single-cell and single-nucleus RNA-seq. Nat. Methods 17, 793–798 (2020). [PMID: 32719530]
  16. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002). [PMID: 12150891]
  17. Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008). [PMID: 18370921]
  18. Schupp, J. C. et al. Integrated single cell atlas of endothelial cells of the human lung. Preprint at https://doi.org/10.1101/2020.10.21.347914 (2020).
  19. Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020). [PMID: 33208946]
  20. Strunz, M. et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 11, 3559 (2020). [PMID: 32678092]
  21. Kobayashi, Y. et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat. Cell Biol. 22, 934–946 (2020). [PMID: 32661339]
  22. Choi, J. et al. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell 27, 366–382.e7 (2020). [PMID: 32750316]
  23. Ziegler, C. G. K. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035.e19 (2020). [PMID: 32413319]
  24. Sungnak, W. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26, 681–687 (2020). [PMID: 32327758]
  25. Muus, C. et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 27, 546–559 (2021). [PMID: 33654293]
  26. Xu, J. et al. SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis. Respir. Res. 21, 182 (2020). [PMID: 32664949]
  27. Grillo, F., Barisione, E., Ball, L., Mastracci, L. & Fiocca, R. Lung fibrosis: an undervalued finding in COVID-19 pathological series. Lancet Infect. Dis. 21, e72 (2021). [PMID: 32735785]
  28. Vaughan, A. E. et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621–625 (2015). [PMID: 25533958]
  29. Fernanda de Mello Costa, M., Weiner, A. I. & Vaughan, A. E. Basal-like progenitor cells: a review of dysplastic alveolar regeneration and remodeling in lung repair. Stem Cell Reports 15, 1015–1025 (2020). [PMID: 33065046]
  30. Wölfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. Nature 581, 465–469 (2020). [PMID: 32235945]
  31. Walsh, K. A. et al. SARS-CoV-2 detection, viral load and infectivity over the course of an infection. J. Infect. 81, 357–371 (2020). [PMID: 32615199]
  32. Blanco-Melo, D. et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181, 1036–1045.e9 (2020). [PMID: 32416070]
  33. Johnson, N. F. Release of lamellar bodies from alveolar type 2 cells. Thorax 35, 192–197 (1980). [PMID: 6247775]
  34. Grant, R. A. et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 590, 635–641 (2021). [PMID: 33429418]
  35. Butler, D. et al. Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions. Nat. Commun. 12, 1660 (2021). [PMID: 33712587]
  36. Park, J. et al. Systemic tissue and cellular disruption from SARS-CoV-2 infection revealed in COVID-19 autopsies and spatial omics tissue maps. Preprint at https://doi.org/10.1101/2021.03.08.434433 (2021).
  37. Rendeiro, A. F. et al. The spatio-temporal landscape of lung pathology in SARS-CoV-2 infection. Preprint at https://doi.org/10.1101/2020.10.26.20219584 (2020).
  38. Karki, R. et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell 184, 149–168.e17 (2021). [PMID: 33278357]
  39. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005). [PMID: 16199517]
  40. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003). [PMID: 12808457]
  41. van de Sandt, C. E. et al. Human CD8 T cells damage noninfected epithelial cells during influenza virus infection in vitro. Am. J. Respir. Cell Mol. Biol. 57, 536–546 (2017). [PMID: 28613916]
  42. Short, K. R. et al. Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions. Eur. Respir. J. 47, 954–966 (2016). [PMID: 26743480]
  43. Lemieux, J. E. et al. Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events. Science 371, eabe3261 (2021). [PMID: 33303686]
  44. Yu, H. H. & Zallen, J. A. Abl and Canoe/Afadin mediate mechanotransduction at tricellular junctions. Science 370, eaba5528 (2020). [PMID: 33243859]
  45. COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet. 28, 715–718 (2020). [DOI: 10.1038/s41431-020-0636-6]
  46. Severe Covid-19 GWAS Group. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 383, 1522–1534 (2020). [DOI: 10.1056/NEJMoa2020283]
  47. Jagadeesh, K. A. et al. Identifying disease-critical cell types and cellular processes across the human body by integration of single-cell profiles and human genetics. Preprint at https://doi.org/10.1101/2021.03.19.436212 (2021).
  48. Melms, J. C. et al. A molecular single-cell lung atlas of lethal COVID-19. Nature https://doi.org/10.1038/s41586-021-03569-1 (2021).
  49. Speranza, E. et al. SARS-CoV-2 infection dynamics in lungs of African green monkeys. Preprint at https://doi.org/10.1101/2020.08.20.258087 (2020).
  50. Desai, N. et al. Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection. Preprint at https://doi.org/10.1101/2020.07.30.20165241 (2020).
  51. Liu, T.-M. et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 126, 61–68 (2015). [PMID: 25972157]
  52. Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018). [PMID: 29409532]
  53. Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019). [PMID: 31740819]
  54. Schiller, H. B. et al. The Human Lung Cell Atlas: a high-resolution reference map of the human lung in health and disease. Am. J. Respir. Cell Mol. Biol. 61, 31–41 (2019). [PMID: 30995076]
  55. Brill, B., Amir, A. & Heller, R. Testing for differential abundance in compositional counts data, with application to microbiome studies. Preprint at https://arxiv.org/abs/1904.08937 (2019).
  56. Ravindra, N. G. et al. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium. Preprint at https://doi.org/10.1101/2020.05.06.081695 (2020).

Grants

  1. /Wellcome Trust
  2. R37 MH107649/NIMH NIH HHS
  3. U01 AA026933/NIAAA NIH HHS
  4. K08 CA222663/NCI NIH HHS
  5. /Howard Hughes Medical Institute
  6. T32 GM007753/NIGMS NIH HHS
  7. P30 DK046200/NIDDK NIH HHS
  8. R01 AA017729/NIAAA NIH HHS
  9. P30 CA013696/NCI NIH HHS
  10. UH3 HL141797/NHLBI NIH HHS
  11. R01 MH107649/NIMH NIH HHS
  12. R01 MH101244/NIMH NIH HHS
  13. R01 AA020744/NIAAA NIH HHS
  14. R37 CA258829/NCI NIH HHS
  15. U54 CA225088/NCI NIH HHS
  16. U01 HG009379/NHGRI NIH HHS
  17. DP2 CA247831/NCI NIH HHS

MeSH Term

Adult
Aged
Aged, 80 and over
Atlases as Topic
Autopsy
Biological Specimen Banks
COVID-19
Endothelial Cells
Epithelial Cells
Female
Fibroblasts
Genome-Wide Association Study
Heart
Humans
Inflammation
Kidney
Liver
Lung
Male
Middle Aged
Myocardium
Organ Specificity
Phagocytes
Pulmonary Alveoli
RNA, Viral
Regeneration
SARS-CoV-2
Single-Cell Analysis
Viral Load

Chemicals

RNA, Viral
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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