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: [email protected].
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.