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

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COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets
Nature ( IF 64.8 ) Pub Date : 2021-04-29 , DOI: 10.1038/s41586-021-03570-8
Toni M Delorey ₁ , Carly G K Ziegler _{2,

3,

4,

5,

6,

7} , Graham Heimberg ₁ , Rachelly Normand _{2,

8,

9,

10,

11} , Yiming Yang _{1,

8} , Åsa Segerstolpe ₁ , Domenic Abbondanza ₁ , Stephen J Fleming _{12,

13} , Ayshwarya Subramanian ₁ , Daniel T Montoro ₂ , Karthik A Jagadeesh ₁ , Kushal K Dey ₁₄ , Pritha Sen _{2,

8,

15,

16} , Michal Slyper ₁ , Yered H Pita-Juárez _{2,

10,

17,

18,

19} , Devan Phillips ₁ , Jana Biermann _{20,

21} , Zohar Bloom-Ackermann ₂₂ , Nikolaos Barkas ₁₂ , Andrea Ganna _{23,

24} , James Gomez ₂₂ , Johannes C Melms _{20,

21} , Igor Katsyv ₂₅ , Erica Normandin _{2,

10} , Pourya Naderi _{10,

17,

18} , Yury V Popov _{10,

26,

27} , Siddharth S Raju _{2,

28,

29} , Sebastian Niezen _{10,

26,

27} , Linus T-Y Tsai _{2,

10,

26,

30,

31} , Katherine J Siddle _{2,

32} , Malika Sud ₁ , Victoria M Tran ₂₂ , Shamsudheen K Vellarikkal _{2,

33} , Yiping Wang _{20,

21} , Liat Amir-Zilberstein ₁ , Deepak S Atri _{2,

33} , Joseph Beechem ₃₄ , Olga R Brook ₃₅ , Jonathan Chen _{2,

36} , Prajan Divakar ₃₄ , Phylicia Dorceus ₁ , Jesse M Engreitz _{2,

37} , Adam Essene _{26,

30,

31} , Donna M Fitzgerald ₃₈ , Robin Fropf ₃₄ , Steven Gazal ₃₉ , Joshua Gould _{1,

12} , John Grzyb ₄₀ , Tyler Harvey ₁ , Jonathan Hecht _{10,

17} , Tyler Hether ₃₄ , Judit Jané-Valbuena ₁ , Michael Leney-Greene ₂ , Hui Ma _{1,

8} , Cristin McCabe ₁ , Daniel E McLoughlin ₃₈ , Eric M Miller ₃₄ , Christoph Muus _{2,

41} , Mari Niemi ₂₃ , Robert Padera _{40,

42,

43} , Liuliu Pan ₃₄ , Deepti Pant _{26,

30,

31} , Carmel Pe'er ₁ , Jenna Pfiffner-Borges ₁ , Christopher J Pinto _{16,

38} , Jacob Plaisted ₄₀ , Jason Reeves ₃₄ , Marty Ross ₃₄ , Melissa Rudy ₂ , Erroll H Rueckert ₃₄ , Michelle Siciliano ₄₀ , Alexander Sturm ₂₂ , Ellen Todres ₁ , Avinash Waghray _{44,

45} , Sarah Warren ₃₄ , Shuting Zhang ₂₂ , Daniel R Zollinger ₃₄ , Lisa Cosimi ₄₆ , Rajat M Gupta _{2,

33} , Nir Hacohen _{2,

9,

47} , Hanina Hibshoosh ₂₅ , Winston Hide _{10,

17,

18,

19} , Alkes L Price ₁₄ , Jayaraj Rajagopal ₃₈ , Purushothama Rao Tata ₄₈ , Stefan Riedel _{10,

17} , Gyongyi Szabo _{2,

10,

26} , Timothy L Tickle _{1,

12} , Patrick T Ellinor ₄₉ , Deborah Hung _{22,

50,

51} , Pardis C Sabeti _{2,

32,

52,

53,

54} , Richard Novak ₅₅ , Robert Rogers _{26,

56} , Donald E Ingber _{41,

55,

57} , Z Gordon Jiang _{10,

26,

27} , Dejan Juric _{16,

38} , Mehrtash Babadi _{12,

13} , Samouil L Farhi ₁ , Benjamin Izar _{20,

21,

58,

59} , James R Stone ₃₆ , Ioannis S Vlachos _{2,

10,

17,

18,

19} , Isaac H Solomon ₄₀ , Orr Ashenberg ₁ , Caroline B M Porter ₁ , Bo Li _{1,

8,

16} , Alex K Shalek _{2,

3,

4,

5,

6,

7,

10,

44,

60,

61,

62} , Alexandra-Chloé Villani _{2,

8,

9,

16} , Orit Rozenblatt-Rosen _{1,

63} , Aviv Regev _{1,

5,

53,

63}

Affiliation

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.
Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Program in Immunology, Harvard Medical School, Boston, MA, USA.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
Genentech, South San Francisco, CA, USA.

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure^1,2,3,4, 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.

中文翻译：

COVID-19 组织图谱揭示 SARS-CoV-2 病理学和细胞靶标

由 SARS-CoV-2 引起的 COVID-19 可导致急性呼吸窘迫综合征和多器官衰竭^1,2,3,4，但对其病理生理学知之甚少。在这里，我们生成了 24 个肺、16 个肾脏、16 个肝脏和 19 个心脏尸检组织样本的单细胞图谱，以及来自死于 COVID-19 的捐赠者的 14 个肺样本的空间图谱。综合计算分析发现肺上皮细胞、免疫细胞和间质细胞发生了实质性重塑，有证据表明组织再生失败有多种途径，包括肺泡 2 型分化缺陷和成纤维细胞扩张以及推定的TP63 ⁺肺内基底样祖细胞。病毒 RNA 在单核吞噬细胞和内皮肺细胞中富集，从而诱导特定的宿主程序。肺部空间分析区分了有和没有病毒 RNA 的肺部区域的炎症宿主反应。对其他组织图谱的分析显示，来自 COVID-19 捐赠者的心脏组织中多种细胞类型发生了转录改变，并根据 COVID-19 全基因组关联研究绘制了与疾病严重程度有关的细胞类型和基因图。我们的基础数据集阐明了全身严重 SARS-CoV-2 感染的生物学效应，这是迈向新疗法的关键一步。

更新日期：2021-04-29

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