Mapping COVID-19 Impact on Lungs at Single-Cell Level
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly affects the lung, resulting in respiratory failure, which is a primary cause of coronavirus disease 2019 (COVID-19) mortality. Nonetheless, the current cellular and molecular knowledge of how SARS-CoV-2 infection drives lung pathology is inadequate. The authors in this study generated multi-omics and single-nucleus transcriptomic atlases of the lungs of COVID-19 patients, which merged histological, transcriptomic, and proteomic analyses. Their work discloses the molecular groundwork of pathological hallmarks linked with SARS-CoV-2 infection in different lung and infiltrating immune cell populations. The study features molecular markers of hyperinflammation, alveolar epithelial cell depletion, vascular alterations, and fibrosis, including parenchymal lung senescence. The authors suggest that the inhibition of FOXO3A might be a potential mechanism for the fibroblast-to-myofibroblast transition in COVID-19 pulmonary fibrosis. This research offers a comprehensive cellular and molecular atlas of COVID-19 lung pathology, advancing our understanding of SARS-CoV-2-related pulmonary injury and paving the way for the identification of potential biomarkers and symptomatic treatments.
Research Criteria
The researchers' idea of this article is to construct a comprehensive multi-omics and single-nucleus transcriptomic atlas of the lungs from the patients with COVID-19 by integrating transcriptomics, proteomics, and histopathological technologies to develop urgently needed and effective targeted symptomatic therapies.
Fig.1 Experimental design. (Wang, 2021)
Sample Type
Nuclei from human lung tissues.
Result—A Single-Cell Transcriptional Atlas of the Lungs of Patients with COVID-19
Pursuing high-resolution molecular profiling of COVID-19 lung pathology, researchers conducted single-nuclei RNA-seq on patient and control lungs, ultimately identifying 28 cell types across four primary categories: epithelial, endothelial, stromal, and immune cells. Consistent with prior findings, ACE2 and TMPRSS2 expression was predominantly observed in epithelial cells, including type I and II alveolar pneumocytes, which are the principal SARS-CoV-2 targets. Notably, an increased presence of ACE2 and/or TMPRSS2 positive epithelial cells emerged in COVID-19 samples, suggesting that the virus enhances infectivity through positive-feedback mechanisms.
Fig.2 snRNA-seq was used to create single-nucleus atlases of the human lung. (Wang, 2021)
Result—Molecular Characterization of COVID-19 Pathology
The authors conducted a study to investigate the cell type-specific transcriptional characteristics of COVID-19 pathogenesis in the lungs of patients. They identified a total of 3,264 COVID-19 DEGs across 28 cell types and found that COVID-19 DEGs were most prevalent in myofibroblasts, alveolar fibroblasts, aerocyte capillary endothelial cells (Cap.EC.a) and AT1. Using modularized analysis, they identified six functional upregulated DEG modules, including ubiquitin-dependent protein catabolic process, surfactant metabolism and lung fibrosis, angiogenesis, and extracellular-matrix organization. They also identified six downregulated DEG modules linked to tissue morphogenesis, structural integrity, and homeostasis. The authors found that pro-fibrotic pathways dominated in fibroblasts and myofibroblasts, whereas cytokine, inflammatory, and chemotaxis pathways were activated in endothelial cells. Furthermore, they identified several transcription factors governing DEGs across cell types, including pro-inflammatory transcription factors and FOXO3, a gene implicated in tissue morphogenesis and regeneration. Overall, the study provides valuable insights into the molecular basis of COVID-19 pathogenesis and its multi-faceted consequences on the lungs of patients.
Fig.3 The transcriptional features of COVID-19 patients' lungs. (Wang, 2021)
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Reference
- Wang, S.; et al. A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nature Cell Biology. 2021, 23(12): 1314-1328.
