Dataset Information

Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1?/Glycolysis-Dependent Axis.

ABSTRACT: COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1? (HIF-1?) and consequently promotes glycolysis. HIF-1?-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1? may have great therapeutic potential for the development of novel drugs to treat COVID-19.

SUBMITTER: Codo AC

PROVIDER: S-EPMC7367032 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis.

Codo Ana Campos AC Davanzo Gustavo Gastão GG Monteiro Lauar de Brito LB de Souza Gabriela Fabiano GF Muraro Stéfanie Primon SP Virgilio-da-Silva João Victor JV Prodonoff Juliana Silveira JS Carregari Victor Corasolla VC de Biagi Junior Carlos Alberto Oliveira CAO Crunfli Fernanda F Jimenez Restrepo Jeffersson Leandro JL Vendramini Pedro Henrique PH Reis-de-Oliveira Guilherme G Bispo Dos Santos Karina K Toledo-Teixeira Daniel A DA Parise Pierina Lorencini PL Martini Matheus Cavalheiro MC Marques Rafael Elias RE Carmo Helison R HR Borin Alexandre A Coimbra Laís Durço LD Boldrini Vinícius O VO Brunetti Natalia S NS Vieira Andre S AS Mansour Eli E Ulaf Raisa G RG Bernardes Ana F AF Nunes Thyago A TA Ribeiro Luciana C LC Palma Andre C AC Agrela Marcus V MV Moretti Maria Luiza ML Sposito Andrei C AC Pereira Fabrício Bíscaro FB Velloso Licio Augusto LA Vinolo Marco Aurélio Ramirez MAR Damasio André A Proença-Módena José Luiz JL Carvalho Robson Francisco RF Mori Marcelo A MA Martins-de-Souza Daniel D Nakaya Helder I HI Farias Alessandro S AS Moraes-Vieira Pedro M PM

Cell metabolism 20200717 3

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of th ...[more]

PMID: 32697943

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Project description:ObjectivesCurrently, cardiovascular risk associated with COVID-19 has been brought to people's attention, but the mechanism is not clear. The aim of this study is to elucidate the mechanisms based on multiple omics data.MethodologyWeighted gene co-expression network analysis (WGCNA) was used to identify key pathways. Combination analysis with aneurysm and atherosclerosis related pathways, hypoxia induced factor-1 (HIF-1) signaling were identified as key pathways of the increased cardiovascular risk associated with COVID-19. ScMLnet algorithm based on scRNA-seq was used to explore the regulation of HIF-1 pathway by intercellular communication. Proteomic analysis was used to detect the regulatory mechanisms between IL18 and HIF-1 signaling pathway. Pseudo time locus analysis was used to study the regulation of HIF1 signaling pathway in macrophages and vascular smooth muscle cells (VSMC) phenotypic transformation. The Virtual Inference of protein-activity by Enriched Regulon (VIPER) analysis was used to study the activity of regulatory proteins. Epigenetic analysis based on methylation revealed epigenetic changes in PBMC after SARS-CoV-2 infection. Potential therapeutic compounds were explored by using Cmap algorithm.ResultsHIF-1 signaling pathway is a common key pathway for aneurysms, atherosclerosis and SARS-CoV-2 infection. Intercellular communication analysis showed that macrophage-derived interleukin-18 (IL-18) activates the HIF-1 signaling pathway through IL18R1. Proteomic analysis showed that IL18/IL18R1 promote NF-κB entry into the nucleus, and activated the HIF-1 signaling pathway. Macrophage-derived IL18 promoted the M1 polarization of macrophages and the syntactic phenotype transformation of VSMCs. MAP2K1 mediates the functional regulation of HIF-1 signaling pathway in various cell types. Epigenetic changes in PBMC after COVID-19 infection are characterized by activation of the type I interferon pathway. MEK inhibitors are the promising compounds for the treatment of HIF-1 overactivation.ConclusionsThe IL18/IL18R1/HIF1A axis is expected to be an therapeutic target for cardiovascular protection after SARS-CoV-2 infection. MEK inhibitors may be an choice for cardiovascular protection after SARS-COV-2 infection.

Dataset Information

Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1?/Glycolysis-Dependent Axis.

Publications

Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis.

Similar Datasets

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