A molecular single-cell lung atlas of lethal COVID-19,Nature

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A molecular single-cell lung atlas of lethal COVID-19
Nature ( IF 64.8 ) Pub Date : 2021-04-29 , DOI: 10.1038/s41586-021-03569-1
Johannes C Melms _{1,

2} , Jana Biermann _{1,

2} , Huachao Huang _{3,

4,

5} , Yiping Wang _{1,

2} , Ajay Nair ₅ , Somnath Tagore ₆ , Igor Katsyv ₇ , André F Rendeiro _{8,

9} , Amit Dipak Amin _{1,

2} , Denis Schapiro _{10,

11} , Chris J Frangieh _{11,

12} , Adrienne M Luoma ₁₃ , Aveline Filliol ₅ , Yinshan Fang _{3,

4,

5} , Hiranmayi Ravichandran _{9,

14,

15} , Mariano G Clausi ₁₆ , George A Alba ₁₇ , Meri Rogava _{1,

2} , Sean W Chen _{1,

2} , Patricia Ho _{1,

2} , Daniel T Montoro _{18,

19} , Adam E Kornberg ₂ , Arnold S Han ₂ , Mathieu F Bakhoum ₂₀ , Niroshana Anandasabapathy _{9,

21,

22} , Mayte Suárez-Fariñas _{23,

24} , Samuel F Bakhoum _{25,

26} , Yaron Bram ₂₇ , Alain Borczuk _{28,

29} , Xinzheng V Guo ₁₆ , Jay H Lefkowitch ₇ , Charles Marboe ₇ , Stephen M Lagana ₇ , Armando Del Portillo ₇ , Emily J Tsai ₅ , Emmanuel Zorn ₂ , Glen S Markowitz ₇ , Robert F Schwabe _{5,

30} , Robert E Schwartz ₂₇ , Olivier Elemento _{8,

9,

15} , Anjali Saqi ₇ , Hanina Hibshoosh ₇ , Jianwen Que _{3,

4,

5,

31} , Benjamin Izar _{1,

2,

31,

32}

Affiliation

Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA.
Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY, USA.
Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA.
Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Center, Boston, MA, USA.
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA.
Human Immune Monitoring Core, Columbia University Irving Medical Center, New York, NY, USA.
Department of Medicine, Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA, USA.
Cell Circuits, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Systems Biology, Harvard Medical School, Boston, MA, USA.
Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
Department of Dermatology, Weill Cornell Medical College, New York, NY, USA.
Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA.
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Institute of Human Nutrition, Columbia University, New York, NY, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
Program for Mathematical Genomics, Columbia University, New York, NY, USA.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection^1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1⁺ pathological fibroblasts³ contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand–receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

中文翻译：

致死性 COVID-19 的分子单细胞肺图谱

呼吸衰竭是严重 SARS-CoV-2 感染患者死亡的主要原因^1,2, 但对肺组织水平的宿主反应知之甚少。在这里，我们对 19 名死于 COVID-19 并接受快速尸检的个体和 7 名对照个体的肺部约 116,000 个细胞核进行了单核 RNA 测序。综合分析确定了细胞组成、转录细胞状态和细胞间相互作用的重大变化，从而提供了对致死性 COVID-19 生物学的深入了解。COVID-19 患者的肺部高度发炎，异常激活的单核细胞衍生巨噬细胞和肺泡巨噬细胞密集浸润，但 T 细胞反应受损。与其他病毒和细菌引起的肺炎相比，单核细胞/巨噬细胞衍生的白介素 1β 和上皮细胞衍生的白介素 6 是 SARS-CoV-2 感染的独特特征。肺泡 2 型细胞采用炎症相关的瞬时祖细胞状态，未能完全转变为肺泡 1 型细胞，导致肺再生受损。此外，我们确定了最近描述的扩展CTHRC1 ⁺病理性成纤维细胞³有助于 COVID-19 中迅速发生的肺纤维化。蛋白质活性和配体-受体相互作用的推断确定了推定的药物靶点以破坏有害回路。该图谱能够剖析致命的 COVID-19，可能有助于我们了解 COVID-19 幸存者的长期并发症，并为治疗发展提供重要资源。

更新日期：2021-04-29

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