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, 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.