A single-cell transcriptomic landscape of the lungs of patients with COVID-19

Abstract

The lung is the primary organ targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making respiratory failure a leading coronavirus disease 2019 (COVID-19)-related mortality. However, our cellular and molecular understanding of how SARS-CoV-2 infection drives lung pathology is limited. Here we constructed multi-omics and single-nucleus transcriptomic atlases of the lungs of patients with COVID-19, which integrate histological, transcriptomic and proteomic analyses. Our work reveals the molecular basis of pathological hallmarks associated with SARS-CoV-2 infection in different lung and infiltrating immune cell populations. We report molecular fingerprints of hyperinflammation, alveolar epithelial cell exhaustion, vascular changes and fibrosis, and identify parenchymal lung senescence as a molecular state of COVID-19 pathology. Moreover, our data suggest that FOXO3A suppression is a potential mechanism underlying the fibroblast-to-myofibroblast transition associated with COVID-19 pulmonary fibrosis. Our work depicts a comprehensive cellular and molecular atlas of the lungs of patients with COVID-19 and provides insights into SARS-CoV-2-related pulmonary injury, facilitating the identification of biomarkers and development of symptomatic treatments.

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

“…Two major cell types in the alveolar gas exchange region, AT2 and AT1 cells, exhibited massive metabolic alterations after SARS-CoV-2 infection. We found that aging was significantly upregulated in AT2 cells, which is consistent with other findings [ 35 ]. Surfactant hemostasis was markedly downregulated in COVID-19 patients (Fig.…”

“…Altogether, these data suggest that both a deficiency and overproduction of mucins contribute to COVID-19 progression. Recent research demonstrates that senescence is a pathological characteristic of the lungs after SARS-CoV-2 infection, which in turn contributes to lung aging and related disorders [ 80 ]. Concordantly, we observed significant upregulated aging in epithelial cells, including club cells, goblet cells, AT1 cells and AT2 cells.…”

Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis

“…In the lung, pulmonary epithelial senescence represents the highest risk of idiopathic pulmonary fibrosis (IPF) [ 1 , 2 ]. Recently it was reported that SARS-Cov-2 viruses cause acute pulmonary virus-induced senescence (VIS), and subsequently fibrosis, illustrating a major mechanism of coronavirus disease 2019 (COVID-19) [ 3 , 4 , 5 ]. VIS features not only alveolar stem cell exhaustion, but also epithelial sloughing, dishevelled repair and fibrogenesis, ultimately resulting in recurrent dyspnea and respiratory failure similar to IPF [ 1 , 3 , 4 , 5 , 6 , 7 , 8 ].…”

“…Recently it was reported that SARS-Cov-2 viruses cause acute pulmonary virus-induced senescence (VIS), and subsequently fibrosis, illustrating a major mechanism of coronavirus disease 2019 (COVID-19) [ 3 , 4 , 5 ]. VIS features not only alveolar stem cell exhaustion, but also epithelial sloughing, dishevelled repair and fibrogenesis, ultimately resulting in recurrent dyspnea and respiratory failure similar to IPF [ 1 , 3 , 4 , 5 , 6 , 7 , 8 ]. As the alveolar epithelia contain predominantly alveolar monolayer squamous epithelial type 1 (AEC1) cells (80%) that are terminally differentiated without replicative capacity and the round cubic AEC2 stem cells (~15%) undertaking self-renewal, proliferation and differentiation to ACE1 [ 9 , 10 ], VIS exemplifies an acutely accelerated form of alveolar senescence in the wake of the cell cycle arrest [ 3 ].…”

“…As the alveolar epithelia contain predominantly alveolar monolayer squamous epithelial type 1 (AEC1) cells (80%) that are terminally differentiated without replicative capacity and the round cubic AEC2 stem cells (~15%) undertaking self-renewal, proliferation and differentiation to ACE1 [ 9 , 10 ], VIS exemplifies an acutely accelerated form of alveolar senescence in the wake of the cell cycle arrest [ 3 ]. However, the mechanism of the accelerated cellular replicative senescence remains to be elucidated in association with widespread alveolar epithelial interstitial damages, epithelial cell repair failure, myofibroblast fibrogenic proliferation and extracellular matrix deposition [ 3 , 4 , 5 ].…”