“…Previous studies reported increased densities of both parenchymal and immune cells in COVID‐19 lung tissues 6 . Here, we observed a positive spatial correlation between cell densities and SARS‐CoV‐2 infection rates especially in tissues 1‐4 (Figure 3D, Supporting Information: Table ), suggesting that increased cell densities might be associated with high infection rates.…”
Section: Resultssupporting
confidence: 73%
“…However, despite intensive studies over the past 3 years, the pathology and underlying molecular mechanism of COVID‐19 remain unclear. Severe COVID‐19 often leads to diffuse alveolar damage (DAD), which presents complex pathological manifestations and is heterogeneous within infected tissues and across patients 6 . However, the dissociation of tissue localization of cells in scRNA‐seq has become a bottleneck to decoding the pathology features at the molecular and cellular levels, and thus hampered the characterization of the immune signatures of the microenvironment for severe COVID‐19.…”
Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID‐19) remain poorly defined. In this study, we investigated the spatial single‐cell molecular and cellular features of postmortem COVID‐19 lung tissues using in situ sequencing (ISS). We detected 10 414 863 transcripts of 221 genes in whole‐slide tissues and segmented them into 1 719 459 cells that were mapped to 18 major parenchymal and immune cell types, all of which were infected by SARS‐CoV‐2. Compared with the non‐COVID‐19 control, COVID‐19 lungs exhibited reduced alveolar cells (ACs) and increased innate and adaptive immune cells. We also identified 19 differentially expressed genes in both infected and uninfected cells across the tissues, which reflected the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that were correlated with high cell densities (HIHD). The HIHD regions expressed high levels of SARS‐CoV‐2 entry‐related factors including ACE2, FURIN, TMPRSS2 and NRP1, and co‐localized with organizing pneumonia (OP) and lymphocytic and immune infiltration, which exhibited increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, mirroring the tissue damage and wound healing processes. Sparse nonnegative matrix factorization (SNMF) analysis of niche features identified seven signatures that captured structure and immune niches in COVID‐19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A primarily progressed with increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B was marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions were marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single‐cell RNA‐seq data (scRNA‐seq) from COVID‐19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations consisting mainly of myofibroblasts. Immunofluorescence staining revealed the activation of IL6‐STAT3 and TGF‐β‐SMAD2/3 pathways in these cells, likely mediating the upregulation of COL1A1 and COL1A2 and excessive fibrosis in the lung tissues. Together, this study provides a spatial single‐cell atlas of cellular and molecular signatures of fatal COVID‐19 lungs, which reveals the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID‐19 lung pathology.
“…Previous studies reported increased densities of both parenchymal and immune cells in COVID‐19 lung tissues 6 . Here, we observed a positive spatial correlation between cell densities and SARS‐CoV‐2 infection rates especially in tissues 1‐4 (Figure 3D, Supporting Information: Table ), suggesting that increased cell densities might be associated with high infection rates.…”
Section: Resultssupporting
confidence: 73%
“…However, despite intensive studies over the past 3 years, the pathology and underlying molecular mechanism of COVID‐19 remain unclear. Severe COVID‐19 often leads to diffuse alveolar damage (DAD), which presents complex pathological manifestations and is heterogeneous within infected tissues and across patients 6 . However, the dissociation of tissue localization of cells in scRNA‐seq has become a bottleneck to decoding the pathology features at the molecular and cellular levels, and thus hampered the characterization of the immune signatures of the microenvironment for severe COVID‐19.…”
Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID‐19) remain poorly defined. In this study, we investigated the spatial single‐cell molecular and cellular features of postmortem COVID‐19 lung tissues using in situ sequencing (ISS). We detected 10 414 863 transcripts of 221 genes in whole‐slide tissues and segmented them into 1 719 459 cells that were mapped to 18 major parenchymal and immune cell types, all of which were infected by SARS‐CoV‐2. Compared with the non‐COVID‐19 control, COVID‐19 lungs exhibited reduced alveolar cells (ACs) and increased innate and adaptive immune cells. We also identified 19 differentially expressed genes in both infected and uninfected cells across the tissues, which reflected the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that were correlated with high cell densities (HIHD). The HIHD regions expressed high levels of SARS‐CoV‐2 entry‐related factors including ACE2, FURIN, TMPRSS2 and NRP1, and co‐localized with organizing pneumonia (OP) and lymphocytic and immune infiltration, which exhibited increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, mirroring the tissue damage and wound healing processes. Sparse nonnegative matrix factorization (SNMF) analysis of niche features identified seven signatures that captured structure and immune niches in COVID‐19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A primarily progressed with increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B was marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions were marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single‐cell RNA‐seq data (scRNA‐seq) from COVID‐19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations consisting mainly of myofibroblasts. Immunofluorescence staining revealed the activation of IL6‐STAT3 and TGF‐β‐SMAD2/3 pathways in these cells, likely mediating the upregulation of COL1A1 and COL1A2 and excessive fibrosis in the lung tissues. Together, this study provides a spatial single‐cell atlas of cellular and molecular signatures of fatal COVID‐19 lungs, which reveals the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID‐19 lung pathology.
“…Previous studies reported increased densities of both parenchymal and immune cells in COVID-19 lung tissues [6]. Here, we observed a positive spatial correlation between cell densities and SARS-CoV-2 infection rates especially in tissues 1-4 (Fig.…”
Section: Spatial Analysis Identifies Regions With High Sars-cov-2 Inf...supporting
confidence: 76%
“…Despite intensive studies in the last 3 years, the pathology and underlying molecular mechanism of COVID-19 remain unclear. Severe COVID-19 is often accompanied by diffuse alveolar damage (DAD) that presents complex pathological manifestations and is heterogeneous within infected tissues and across patients [6]. The dissociation of tissue localization of cells in scRNA-seq has become a bottleneck to decoding the pathology features at the molecular and cellular levels and failed to reveal the immune signatures of the microenvironment for severe COVID-19.…”
Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. Here, we examined postmortem COVID-19 lung tissues by spatial single-cell transcriptome analysis (SSCTA). We identified 18 major parenchymal and immune cell types, all of which are infected by SARS-CoV-2. Compared to the non-COVID-19 control, COVID-19 lungs have reduced alveolar cells (ACs), and increased innate and adaptive immune cells. Additionally, 19 differentially expressed genes in both infected and uninfected cells across the tissues mirror the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that are correlated with high cell densities (HIHD). The HIHD regions express high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2, and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration that have increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, echoing the tissue damage and wound healing processes. Sparse non-negative matrix factorization (SNMF) analysis of neighborhood cell type composition (NCTC) features identified 7 signatures that capture structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A progresses with primarily increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B is marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions are marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations primarily consisting of myofibroblasts. Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-β-SMAD2/3 pathways in these cells, which likely mediate the upregulation of COL1A1 and COL1A2, and excessive fibrosis in the lung tissues. Together, this study provides an SSCTA atlas of cellular and molecular signatures of fatal COVID-19 lungs, revealing the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology.
“… 1 , 2 In more severe COVID-19, pulmonary injury progresses to acute respiratory distress syndrome (ARDS), characterised by interstitial and alveolar infiltrates, hypoxaemia and diffuse alveolar damage. 3 ( Fig. 1 ) Figure 1 Study flow diagram.…”
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