Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

ABSTRACT: COVID-19-induced Ã¢Â€Â˜acute respiratory distress syndromeÃ¢Â€Â™ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

PROVIDER: EGAS00001005634 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

Proteomics and phosphoproteomics of SARS-CoV-2 and IAV treated APCs

Project description:The clinical course of SARS-CoV-2 infection is highly variable with a subset of patients developing severe COVID-19 and acute respiratory distress syndrome (ARDS). COVID-19 induced lung injury and respiratory failure appears to be driven by dysregulated immune responses, yet the exact mechanisms remain unknown. Here, we analyzed monocytes isolated from healthy donors treated with SARS-CoV-2, influenza A (Panama strain) or TLR7/8 agonist R848. Notably, overnight exposure to SARS-CoV-2, but not influenza A virus, induced a profibrotic signature, characterized by high expression of known fibrogenic factors like TGFB1, SPP1 and LGMN, and showed highly significant similarity with profibrotic macrophage populations identified in idiopathic pulmonary fibrosis (IPF). In conclusion, SARS-CoV-2 triggers profibrotic macrophage responses, and ARDS-associated lung fibrosis.

2021-11-29 | PXD022709 | Pride

Persistent viral activity, cytokine storm and lung fibrosis in severe COVID-19

Project description:Severe COVID-19 may progress into acute respiratory distress syndrome (ARDS) with high mortality risk. Its exact pathological mechanism, therapeutic obstacles and the clinical sequelae are critical and unresolved issues. Here, we reported a representative COVID-19 induced ARDS case experienced initially stable, then suddenly deteriorating up to final respiratory failure courses, until his death despite of lung transplantation. His lung pathology showed necrosis of parenchymal tissues, extensive immune cell infiltration and lung fibrosis. Single-cell RNA sequencing revealed various immune cell populations were largely expanded in his lung, and manifested inflammatory/activated functions. We also showed that cell-crosstalk between lung macrophages and fibroblasts promoted pulmonary fibrosis through IL-1B and TGF-Β signaling pathways. Although SARS-CoV-2 RNA remained undetectable in his respiratory tract specimens including BALF at the later stage of his disease, the presence of SARS-CoV-2 was definitely confirmed in his lung tissues. Thus, this case indicates the pathological mechanism of severe COVID-19 includes pulmonary SARS-CoV-2 persistence, deranged inflammation and the extensive lung fibrosis which set the barriers for effective treatments and indicate potential health complications for severe COVID-19 patients.

2020-12-01 | GSE149878 | GEO

Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid in severe COVID-19 and SARS-CoV-2 stimulated classical blood monocytes

Project description:We analyzed pulmonary monocyte and macrophage responses as well as and pulmonary pathology in two cohorts of patients with COVID-19 associated ARDS. Monocyte-derived macrophages accumulated in the lung during ARDS and acquired a profibrotic signature, characterized by high expression of known fibrogenic factors like TGFB1, SPP1 and LGMN. COVID-19 associated macrophages showed highly significant transcriptional similarity with profibrotic macrophage populations identified in idiopathic pulmonary fibrosis (IPF). Notably, overnight exposure to SARS-CoV-2, but not influenza A virus or viral RNA analogues, induced a similar phenotype in human monocytes from healthy volunteers in vitro. Patients with severe COVID-19 associated ARDS showed clear clinical, radiographic and histopathological features of scarring and fibrotic tissue remodeling. In conclusion, SARS-CoV-2 triggers profibrotic macrophage responses, fibroproliferative ARDS, and lung fibrosis

| EGAS00001004928 | EGA

Emergence of CCL18- and IFI27-expressing macrophages in aging lungs, and potential roles for alveolar type 2 cell AGTR2 and macrophage BSG and CTSL expression in COVID-19

Project description:Aging lungs are associated with several lung diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pneumonia. This latter age-associated complication has been particularly prominent in the recent COVID-19 pandemic. We have analyzed carefully selected normal lung samples from human subjects at different ages simultaneously using hashtag-labeled samples and single cell RNA-sequencing technology. We identify prominent changes in macrophage populations in lungs from older individuals, including an emerging populations of macrophages expressing IFI27 and other interferon-regulated genes. We also see increased gene expression of CCL18 and other chemokines in FABP4+/alveolar and SPP1+/interstitial macrophages. All three macrophage populations highly express BSG/CD147a putative SARS-CoV-2 receptor and CSTL, a gene associated with SARS-CoV-2 activation. ACE2, the SARS-CoV-2 receptor, and TMPSS2, a SARS-CoV2 protease activator, are both expressed highly on AT2 cells with increased expression on AT2 cells from older lungs. AGTR2, a recently proposed alternative receptor for SARS-CoV-2 was highly selectively and markedly upregulated by AT2 cells from aging lungs. Thus, our data show increased lung expression of ACE2, AGTR2 and TMPRSS2 by AT2 cells with aging. In addition, our data indicate a distinct molecular pathway for lung SARS-CoV-2 infection of lung macrophages. Macrophages may contribute to increased COVID-19 severity in older patients by specific macrophage populations poised to contribute to the cytokine storm, in particular through enhanced interferon responses and interleukin-6 production.

2024-05-06 | GSE150148 | GEO

High titers and low fucosylation of early anti-SARS-CoV-2 IgG promote hyper-inflammation by anti-inflammatory macrophages (MIL10)

Project description:Patients diagnosed with coronavirus disease 2019 (COVID-19) mostly become critically ill around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces hyper-inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the Fc tail. Notably, low anti-spike IgG fucosylation normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the hyper-inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of the kinase, Syk.

2021-04-30 | E-MTAB-10431 | biostudies-arrayexpress

Lung transplantation for patients with severe COVID-19

Project description:Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19-associated respiratory failure. Concerns limiting transplant include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and potential risk for allograft infection by pathogens associated with ventilator-associated pneumonia in the native lung. Most importantly, the native lung might recover, resulting in long-term outcomes preferable to transplant. Here, we report results of the first successful lung transplantation procedures in patients with non-resolving COVID-19-associated respiratory failure in the United States. We performed sm-FISH to detect both positive and negative strands of SARS-CoV-2 RNA in the explanted lung tissue, extracellular matrix imaging using SHIELD tissue clearance, and single cell RNA-Seq on explant and warm post-mortem lung biopsies from patients who died from severe COVID-19 pneumonia. Lungs from patients with prolonged COVID-19 were free of virus but pathology showed extensive evidence of injury and fibrosis which resembled end-stage pulmonary fibrosis. We used a machine learning approach to project single cell RNA-Seq data from patients with late stage COVID-19 onto a single cell atlas of pulmonary fibrosis, revealing similarities across cell lineages. There was no recurrence of SARS-CoV-2 or pathogens associated with pre-transplant ventilator associated pneumonias following transplantation. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is the only option for survival.

2020-10-28 | GSE158127 | GEO

SnoRNAs and miRNAs expression profiles underlying COVID-19 disease severity

Project description:The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical manifestations in disease-ridden patients. Differences in the severity of COVID-19 ranges from asymptomatic infections and mild cases to the severe form, leading to acute respiratory distress syndrome (ARDS) and multiorgan failure with poor survival. MiRNAs can regulate various cellular processes, including proliferation, apoptosis, and differentiation, by binding to the 3′UTR of target mRNAs inducing their degradation, thus serving a fundamental role in post-transcriptional repression. Alterations of miRNA levels in the blood have been described in multiple inflammatory and infectious diseases, including SARS-related coronaviruses. We used microarrays to delineate the miRNAs and snoRNAs signature in the peripheral blood of severe COVID-19 cases (n=9), as compared to mild (n=10) and asymptomatic (n=10) patients, and identified differentially expressed transcripts in severe versus asymptomatic, and others in severe versus mild COVID-19 cases. A cohort of 29 male age-matched patients were selected. All patients were previously diagnosed with COVID-19 using TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, Massachusetts), or Cobas SARS-CoV-2 Test (Roche Diagnostics, Rotkreuz, Switzerland), with a CT value < 30. Additional criterion for selection was age between 35 and 75 years. Participants were grouped into severe, mild and asymptomatic. Classifying severe cases was based on requirement of high-flow oxygen support and ICU admission (n=9). Whereas mild patients were identified based on symptoms and positive radiographic findings with pulmonary involvement (n=10). Patients with no clinical presentation were labelled as asymptomatic cases (n=10).

2022-03-01 | E-MTAB-10970 | biostudies-arrayexpress

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [scRNA-seq]

Project description:Recent studies of severe acute inflammatory lung disease including COVID-19 have identified macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 was among the strongest upregulated microRNAs in COVID-19 and in mice with acute inflammatory lung damage and was the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of an oligonucleotide inhibitor of microRNA-21 to trimannose achieved rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reversed pathological activation of macrophages and prevented pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevented the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.

2023-07-12 | GSE235135 | GEO

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [transcriptome_mouse]

2023-07-12 | GSE235134 | GEO

Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage [transcriptome_human_COVID]

2023-07-12 | GSE235133 | GEO