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

Johannes C. Melms, Jana Biermann, Huachao Huang, Yiping Wang, Ajay Nair, Somnath Tagore, Igor Katsyv, André F. Rendeiro, Amit Dipak Amin, Denis Schapiro, Chris J. Frangieh, Adrienne M. Luoma, Aveline Filliol, Yinshan Fang, Hiranmayi Ravichandran, Mariano G. Clausi, George A. Alba, Meri Rogava, Sean W. Chen, Patricia HoDaniel T. Montoro, Adam E. Kornberg, Arnold S. Han, Mathieu F. Bakhoum, Niroshana Anandasabapathy, Mayte Suárez-Fariñas, Samuel F. Bakhoum, Yaron Bram, Alain Borczuk, Xinzheng V. Guo, Jay H. Lefkowitch, Charles Marboe, Stephen M. Lagana, Armando Del Portillo, Emmanuel Zorn, Glen S. Markowitz, Robert F. Schwabe, Robert E. Schwartz, Olivier Elemento, Anjali Saqi, Hanina Hibshoosh, Jianwen Que, Benjamin Izar

Research output: Contribution to journalArticlepeer-review

226 Scopus citations


Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, 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.

Original languageEnglish
Pages (from-to)114-119
Number of pages6
Issue number7865
StatePublished - 1 Jul 2021
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We are grateful to all donors and their families. This work is part of the Human Cell Atlas (www.humancellatlas.org/publications). We thank J. Bhattacharya, I. Tabas, A. Tall and S. Roth for discussions. B.I. is supported by National Institute of Health (NIH) National Cancer Institute (NCI) grants K08CA222663, R37CA258829 and U54CA225088, a FastGrant, the Burroughs Wellcome Fund Career Award for Medical Scientists and the Louis V. Gerstner, Jr. Scholars Program. J.Q. is supported by R01HL152293 and R01HL132996. H. Huang is supported by the Department of Defense (DoD) Discovery Award W81XWH-21-1-0196. A.R. is supported by an NCI T32CA203702 grant. O.E. is supported by Volastra, Janssen and Eli Lilly research grants, NIH grants UL1TR002384, R01CA194547, and Leukemia and Lymphoma Society SCOR 7012-16, SCOR 7021-20 and SCOR 180078-02 grants. R.E.S. is supported by NIH grants NCI R01CA234614, NIAID R01AI107301, NIDDK R01DK121072 and RO3DK117252, and is an Irma Hirschl Trust Research Award Scholar. D.S. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRQ-03-20). This research was funded in part through the NIH Support Grant S10RR027050 for flow cytometry analysis and the NIH/NCI Cancer Center Support Grant P30CA013696 at Columbia University Genetically Modified Mouse Model Shared Resource, Molecular Pathology Shared Resource and its Tissue Bank.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.


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