Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages
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PROVIDER: PRJNA817209 | ENA |
REPOSITORIES: ENA
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Project description:Scarce ACE2 expression limits alveolar SARS-CoV-2 permissiveness and related tissue damage. Instead, non-productive virus uptake by alveolar macrophages leads to a specific pulmonary immune activation. COVID-19 ARDS is most likely caused by immunopathogenesis rather than alveolar viral damage.
2022-05-30 | GSE198864 | GEO
Project description:BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive.MethodsSpectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results.ResultsWe provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection.ConclusionsCollectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.
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Project description:The homologous Ace2 and Swi5 transcription factors of Saccharomyces cerevisiae have identical DNA-binding domains, and both are cell cycle regulated. There are common target genes, as well as genes activated only by Ace2 and other genes activated only by Swi5. Keywords: genetic modification RNA was isolated from four strains: wild type, ace2 gene deletion, swi5 gene deletion, and the ace2 swi5 double gene deletion. RNAs from the three mutant strains were compared to wild type RNA in a microarray hybridization experiment.
2008-05-13 | E-GEOD-11380 | biostudies-arrayexpress
Project description:In a screen of human upper airway cell lines, we identified the H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite no evidence of ACE2 or TMPRSS2 expression. Temporally resolved transcriptomic and proteomic profiling of H522 cells revealed consistent alterations in the antiviral host cell response, including marked activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection of H522 cells. The natural permissiveness of H522 cells to SARS-CoV-2 infection despite no requirement for ACE2 implies the utilization of an alternative receptor and viral entry mechanism which may have important implications for SARS-CoV-2 pathogenesis in humans.
2022-03-07 | PXD023754 | Pride
Project description:BMPR2 mutation causes pulmonary arterial hypertension (PAH); ACE2 treatment can resolve established BMPR2-mediated PAH. The purpose of this study was to uncover the molecular mechanism behind this. Four groups: +/- ACE2 and +/- BMPR2 transgene, two arrays each, each array a pool of three animals.
2010-08-24 | E-GEOD-21583 | biostudies-arrayexpress
Project description:Ace2 transcription factor family genes are found in many fungal genomes and are required for regulation of expression of genes involved in cell separation. We used transcriptional profiling to identify the targets of Ace2 in Candida albicans, and we show that these include several cell wall components, such as glucanases and glycosylphosphatidylinositol-anchored proteins. Expression is downregulated in ace2 deletion mutants in both yeast and hyphal cells. In addition, deleting ace2 results in dramatic changes in expression of metabolic pathways. Expression of glycolytic enzymes is reduced, while expression of respiratory genes (including those involved in the tricarboxylic acid cycle, oxidative phosphorylation, and ATP synthesis) is increased. Similar changes occur in both yeast and hyphal cells. In contrast, genes required for acetyl-coenzyme A and lipid metabolism are upregulated in an ace2 deletion mutant grown predominantly as yeast cells but are downregulated in hyphae. These results suggest that in wild-type strains, Ace2 acts to increase glycolysis and reduce respiration. This is supported by the observation that deleting ace2 results in increased resistance to antimycin A, a drug that inhibits respiration. We also show that Ace2 is required for filamentation in response to low oxygen concentrations (hypoxia). We suggest that filamentation is induced in wild-type cells by reducing respiration (using low oxygen or respiratory drugs) and that mutants with increased respiratory activity fail to undergo filamentation under these conditions. This SuperSeries is composed of the SubSeries listed below.
2007-02-23 | GSE7105 | GEO
Project description:In this study a gene expression (i.e., RNAseq) analysis was performed in HEK293T-ACE2 cellular model upon infection with viral particle belonging to VOC Delta (MOI: 0.026) for 24 hours in order to have a global picture of the transcriptome landscape in response to early phase of infection of SARS-CoV-2 ( VOC Delta infection and to evaluate the role of Ca2+ in HEK293-ACE2 cellular model and transfer to homeostasis in SARS-COV-2 patients (by Pasqualino de Antonellis1-2* and Veronica Ferrucci 1-2* (first authors) et al. and Massimo Zollo1-2# (corresponding author). Manuscript in preparation 2022 July 15th 2022. Short title "ATP2B1 (PMCA1), regulated by FOXO3, influences susceptibility to severe COVID19".
2022-12-01 | E-MTAB-11973 | biostudies-arrayexpress
Project description:Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury Forty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. The gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. Sample vs reference, total RNA isolated from peripheral blood mononuclear cells (PBMC), 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls
2010-10-27 | E-GEOD-19617 | biostudies-arrayexpress
Project description:The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally, but with widely variable outcomes. The development of severe disease and mortality is higher in older individuals, males and those with other co-morbidities, and may vary across ethnic groups. However, so far, no host genetic factor has been clearly associated with susceptibility and development of severe disease. To understand the impact of host genetics on expression of ACE2 (SARS-CoV-2 receptor) during RNA virus infection we performed a GWAS for ACE2 expression in HCV-infected liver tissue from 195 individuals. We discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. ACE2 expression was regulated additionally by age, with a subsidiary effect of co-morbidity. The IFNL locus controlled expression of a gene network incorporating many well-known interferon-stimulated genes which anti-correlated with ACE2 transcript levels. The same anti-correlation was found in the gastrointestinal tract, a site of SARS-CoV-2 replication where inflammation driven interferon-stimulated genes are negatively correlated with ACE2 expression. The interferon dependent regulation of ACE2 was identified in a murine model of SARS-CoV-1 suggesting conserved regulation of ACE2 across species. Polymorphisms in the IFNL region, as well as age, may impact not only on classical antiviral responses but also on ACE2 with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.
2020-04-30 | GSE149601 | GEO