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

Nature. 2021 Jul;595(7865):114-119. doi: 10.1038/s41586-021-03569-1. Epub 2021 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alveolar Epithelial Cells / pathology
  • Alveolar Epithelial Cells / virology
  • Atlases as Topic
  • Autopsy
  • COVID-19 / immunology
  • COVID-19 / pathology*
  • COVID-19 / virology*
  • Case-Control Studies
  • Female
  • Fibroblasts / pathology
  • Fibrosis / pathology
  • Fibrosis / virology
  • Humans
  • Inflammation / pathology
  • Inflammation / virology
  • Lung / pathology*
  • Macrophages / pathology
  • Macrophages / virology
  • Macrophages, Alveolar / pathology
  • Macrophages, Alveolar / virology
  • Male
  • Middle Aged
  • Plasma Cells / immunology
  • SARS-CoV-2 / pathogenicity*
  • Single-Cell Analysis*
  • T-Lymphocytes / immunology