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 Portillo, Emily J. Tsai, Emmanuel Zorn, Glen S. Markowitz, Robert F. Schwabe, Robert E. Schwartz, Olivier Elemento, Anjali Saqi, Hanina Hibshoosh, Jianwen Que () and Benjamin Izar ()
Additional contact information
Johannes C. Melms: Columbia University Irving Medical Center
Jana Biermann: Columbia University Irving Medical Center
Huachao Huang: Columbia University Irving Medical Center
Yiping Wang: Columbia University Irving Medical Center
Ajay Nair: Columbia University Irving Medical Center
Somnath Tagore: Columbia University Irving Medical Center
Igor Katsyv: Columbia University Irving Medical Center
André F. Rendeiro: Weill Cornell Medicine
Amit Dipak Amin: Columbia University Irving Medical Center
Denis Schapiro: Harvard Medical School
Chris J. Frangieh: Broad Institute of MIT and Harvard
Adrienne M. Luoma: Dana-Farber Cancer Center
Aveline Filliol: Columbia University Irving Medical Center
Yinshan Fang: Columbia University Irving Medical Center
Hiranmayi Ravichandran: Weill Cornell Medicine
Mariano G. Clausi: Columbia University Irving Medical Center
George A. Alba: Massachusetts General Hospital
Meri Rogava: Columbia University Irving Medical Center
Sean W. Chen: Columbia University Irving Medical Center
Patricia Ho: Columbia University Irving Medical Center
Daniel T. Montoro: Broad Institute of MIT and Harvard
Adam E. Kornberg: Columbia University Irving Medical Center
Arnold S. Han: Columbia University Irving Medical Center
Mathieu F. Bakhoum: University of California San Diego
Niroshana Anandasabapathy: Weill Cornell Medicine
Mayte Suárez-Fariñas: Icahn School of Medicine at Mount Sinai
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Yaron Bram: Weill Cornell Medicine
Alain Borczuk: Weill Cornell Medicine
Xinzheng V. Guo: Columbia University Irving Medical Center
Jay H. Lefkowitch: Columbia University Irving Medical Center
Charles Marboe: Columbia University Irving Medical Center
Stephen M. Lagana: Columbia University Irving Medical Center
Armando Portillo: Columbia University Irving Medical Center
Emily J. Tsai: Columbia University Irving Medical Center
Emmanuel Zorn: Columbia University Irving Medical Center
Glen S. Markowitz: Columbia University Irving Medical Center
Robert F. Schwabe: Columbia University Irving Medical Center
Robert E. Schwartz: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Anjali Saqi: Columbia University Irving Medical Center
Hanina Hibshoosh: Columbia University Irving Medical Center
Jianwen Que: Columbia University Irving Medical Center
Benjamin Izar: Columbia University Irving Medical Center

Nature, 2021, vol. 595, issue 7865, 114-119

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03569-1

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