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

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; Zorn, Emmanuel; Markowitz, Glen S; Schwabe, Robert F; Schwartz, Robert E; Elemento, Olivier; Saqi, Anjali; Hibshoosh, Hanina; Que, Jianwen; Izar, Benjamin

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, yet the host response at the lung tissue-level is poorly understood. Here, we performed single-nucleus RNA-sequencing of ~116,000 nuclei of lungs from 19 COVID-19 decedents who underwent rapid autopsy and 7 control lungs. Integrated analyses revealed significant alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, providing insights into the biology of lethal COVID-19. COVID-19 lungs were highly inflamed with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but demonstrated impaired T cell responses. Monocyte/macrophage-derived IL-1β and epithelial cell-derived IL-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 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.