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

Cell Metab. 2020 Sep 1;32(3):437-446.e5. doi: 10.1016/j.cmet.2020.07.007.

Ana Campos Codo ¹, Gustavo Gastão Davanzo ¹, Lauar de Brito Monteiro ¹, Gabriela Fabiano de Souza ², Stéfanie Primon Muraro ², João Victor Virgilio-da-Silva ¹, Juliana Silveira Prodonoff ¹, Victor Corasolla Carregari ³, Carlos Alberto Oliveira de Biagi Junior ⁴, Fernanda Crunfli ³, Jeffersson Leandro Jimenez Restrepo ⁵, Pedro Henrique Vendramini ³, Guilherme Reis-de-Oliveira ³, Karina Bispo Dos Santos ², Daniel A Toledo-Teixeira ², Pierina Lorencini Parise ², Matheus Cavalheiro Martini ², Rafael Elias Marques ⁶, Helison R Carmo ⁷, Alexandre Borin ⁶, Laís Durço Coimbra ⁶, Vinícius O Boldrini ², Natalia S Brunetti ², Andre S Vieira ⁸, Eli Mansour ⁹, Raisa G Ulaf ⁹, Ana F Bernardes ⁹, Thyago A Nunes ⁹, Luciana C Ribeiro ⁹, Andre C Palma ⁹, Marcus V Agrela ⁹, Maria Luiza Moretti ⁹, Andrei C Sposito ⁷, Fabrício Bíscaro Pereira ¹⁰, Licio Augusto Velloso ¹¹, Marco Aurélio Ramirez Vinolo ¹², André Damasio ¹³, José Luiz Proença-Módena ², Robson Francisco Carvalho ¹⁴, Marcelo A Mori ¹⁵, Daniel Martins-de-Souza ¹⁶, Helder I Nakaya ⁵, Alessandro S Farias ¹², Pedro M Moraes-Vieira ¹⁷

Affiliations

1 Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
2 Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
3 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
4 Department of Genetics at Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil.
5 Department of Clinical and Toxicological analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
6 Brazilian Biosciences National Laboratory (LNBio), Campinas, São Paulo, Brazil.
7 Department of Clinical Medicine, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
8 Department of Animal Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
9 Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
10 Hematology and Hemotherapy Center University of Campinas, Campinas, São Paulo, Brazil.
11 Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil.
12 Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, São Paulo, Brazil.
13 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, São Paulo, Brazil.
14 Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
15 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, São Paulo, Brazil.
16 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, São Paulo, Brazil; D'Or Institute for Research and Education (IDOR), São Paulo, Brazil; Instituto Nacional de Biomarcadores em Neuropsiquiatria, Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brazil.
17 Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil; Experimental Medicine Research Cluster (EMRC), University of Campinas, São Paulo, Brazil. Electronic address: pmvieira@unicamp.br.

PMID: 32697943 DOI: 10.1016/j.cmet.2020.07.007

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-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 Infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.

Keywords

Covid-19; HIF-1alpha; SARS-CoV-2; diabetes; glycolysis; inflammation; interferon; metabolism; mitochondria; monocyte.

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