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 Ho; Daniel 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

doi:10.1038/s41586-021-03569-1

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 journal › Article › peer-review

356 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	114-119
Number of pages	6
Journal	Nature
Volume	595
Issue number	7865
DOIs	https://doi.org/10.1038/s41586-021-03569-1
State	Published - 1 Jul 2021
Externally published	Yes

Bibliographical note

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

Funding

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.

Funders	Funder number
National Institutes of Health
U.S. Department of Defense	W81XWH-21-1-0196, UL1TR002384
National Cancer Institute	R01CA194547, U54CA225088, P30CA013696, T32CA203702, R01CA234614, K08CA222663, R37CA258829
National Institute of Allergy and Infectious Diseases	R01AI107301
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK121072, RO3DK117252
Burroughs Wellcome Fund	R01HL152293, R01HL132996
Damon Runyon Cancer Research Foundation	DRQ-03-20, S10RR027050
Leukemia and Lymphoma Society	SCOR 7021-20, SCOR 7012-16, SCOR 180078-02
Columbia University
Irma T. Hirschl Trust

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Melms, J. C., Biermann, J., Huang, H., Wang, Y., Nair, A., Tagore, S., Katsyv, I., Rendeiro, A. F., Amin, A. D., Schapiro, D., Frangieh, C. J., Luoma, A. M., Filliol, A., Fang, Y., Ravichandran, H., Clausi, M. G., Alba, G. A., Rogava, M., Chen, S. W., ... Izar, B. (2021). A molecular single-cell lung atlas of lethal COVID-19. Nature, 595(7865), 114-119. https://doi.org/10.1038/s41586-021-03569-1

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title = "A molecular single-cell lung atlas of lethal COVID-19",

abstract = "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.",

author = "Melms, {Johannes C.} and Jana Biermann and Huachao Huang and Yiping Wang and Ajay Nair and Somnath Tagore and Igor Katsyv and Rendeiro, {Andr{\'e} F.} and Amin, {Amit Dipak} and Denis Schapiro and Frangieh, {Chris J.} and Luoma, {Adrienne M.} and Aveline Filliol and Yinshan Fang and Hiranmayi Ravichandran and Clausi, {Mariano G.} and Alba, {George A.} and Meri Rogava and Chen, {Sean W.} and Patricia Ho and Montoro, {Daniel T.} and Kornberg, {Adam E.} and Han, {Arnold S.} and Bakhoum, {Mathieu F.} and Niroshana Anandasabapathy and Mayte Su{\'a}rez-Fari{\~n}as and Bakhoum, {Samuel F.} and Yaron Bram and Alain Borczuk and Guo, {Xinzheng V.} and Lefkowitch, {Jay H.} and Charles Marboe and Lagana, {Stephen M.} and {Del Portillo}, Armando and Emmanuel Zorn and Markowitz, {Glen S.} and Schwabe, {Robert F.} and Schwartz, {Robert E.} and Olivier Elemento and Anjali Saqi and Hanina Hibshoosh and Jianwen Que and Benjamin Izar",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = jul,

day = "1",

doi = "10.1038/s41586-021-03569-1",

language = "אנגלית",

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Melms, JC, Biermann, J, Huang, H, Wang, Y, Nair, A, Tagore, S, Katsyv, I, Rendeiro, AF, Amin, AD, Schapiro, D, Frangieh, CJ, Luoma, AM, Filliol, A, Fang, Y, Ravichandran, H, Clausi, MG, Alba, GA, Rogava, M, Chen, SW, Ho, P, Montoro, DT, Kornberg, AE, Han, AS, Bakhoum, MF, Anandasabapathy, N, Suárez-Fariñas, M, Bakhoum, SF, Bram, Y, Borczuk, A, Guo, XV, Lefkowitch, JH, Marboe, C, Lagana, SM, Del Portillo, A, Zorn, E, Markowitz, GS, Schwabe, RF, Schwartz, RE, Elemento, O, Saqi, A, Hibshoosh, H, Que, J & Izar, B 2021, 'A molecular single-cell lung atlas of lethal COVID-19', Nature, vol. 595, no. 7865, pp. 114-119. https://doi.org/10.1038/s41586-021-03569-1

TY - JOUR

T1 - A molecular single-cell lung atlas of lethal COVID-19

AU - Melms, Johannes C.

AU - Biermann, Jana

AU - Huang, Huachao

AU - Wang, Yiping

AU - Nair, Ajay

AU - Tagore, Somnath

AU - Katsyv, Igor

AU - Rendeiro, André F.

AU - Amin, Amit Dipak

AU - Schapiro, Denis

AU - Frangieh, Chris J.

AU - Luoma, Adrienne M.

AU - Filliol, Aveline

AU - Fang, Yinshan

AU - Ravichandran, Hiranmayi

AU - Clausi, Mariano G.

AU - Alba, George A.

AU - Rogava, Meri

AU - Chen, Sean W.

AU - Ho, Patricia

AU - Montoro, Daniel T.

AU - Kornberg, Adam E.

AU - Han, Arnold S.

AU - Bakhoum, Mathieu F.

AU - Anandasabapathy, Niroshana

AU - Suárez-Fariñas, Mayte

AU - Bakhoum, Samuel F.

AU - Bram, Yaron

AU - Borczuk, Alain

AU - Guo, Xinzheng V.

AU - Lefkowitch, Jay H.

AU - Marboe, Charles

AU - Lagana, Stephen M.

AU - Del Portillo, Armando

AU - Zorn, Emmanuel

AU - Markowitz, Glen S.

AU - Schwabe, Robert F.

AU - Schwartz, Robert E.

AU - Elemento, Olivier

AU - Saqi, Anjali

AU - Hibshoosh, Hanina

AU - Que, Jianwen

AU - Izar, Benjamin

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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.

AB - 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.

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

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