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Melms, Johannes C; Biermann, Jana; Huang, Huachao; Wang, Yiping; Nair, Ajay; Tagore, Somnath; Katsyv, Igor; Rendeiro, André F; Amin, Amit Dipak; Schapiro, Denis; Frangieh, Chris J; Luoma, Adrienne M; Filliol, Aveline; Fang, Yinshan; Ravichandran, Hiranmayi; Clausi, Mariano G; Alba, George A; Rogava, Meri; Chen, Sean W; Ho, Patricia; Montoro, Daniel T; Kornberg, Adam E; Han, Arnold S; Bakhoum, Mathieu F; Anandasabapathy, Niroshana; Suárez-Fariñas, Mayte; Bakhoum, Samuel F; Bram, Yaron; Borczuk, Alain; Guo, Xinzheng V; Lefkowitch, Jay H; Marboe, Charles; Lagana, Stephen M; Del Portillo, Armando; Tsai, Emily J; Zorn, Emmanuel; Markowitz, Glen S; Schwabe, Robert F; Schwartz, Robert E; Elemento, Olivier; Saqi, Anjali; Hibshoosh, Hanina; Que, Jianwen; Izar, Benjamin
Nature (London), 07/2021, Volume: 595, Issue: 7865Journal Article
Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection , 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 fibroblasts 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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