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Friday, July 17, 2020

Elevated glucose levels favor SARS-CoV-2 infection and monocyte response via HIF-1α/glycolysis dependent axis


Author Footnotes
16 These authors contributed equally to this work.
Ana Campos Codo
Footnotes
16 These authors contributed equally to this work.
Affiliations
Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Author Footnotes
    16 These authors contributed equally to this work.
    Gustavo Gastão Davanzo
    Footnotes
    16 These authors contributed equally to this work.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Author Footnotes
    16 These authors contributed equally to this work.
    Lauar de Brito Monteiro
    Footnotes
    16 These authors contributed equally to this work.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Gabriela Fabiano de Souza
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Stéfanie Primon Muraro
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • João Victor Virgilio-da-Silva
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Juliana Silveira Prodonoff
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Victor Corasolla Carregari
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Carlos Alberto Oliveira de Biagi Junior
    Affiliations
    Department of Genetics at Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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  • Fernanda Crunfli
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Jeffersson Leandro Jimenez Restrepo
    Affiliations
    Department of Clinical and Toxicological analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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  • Pedro Henrique Vendramini
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Guilherme Reis-de-Oliveira
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Karina Bispo dos Santos
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Daniel Augusto de Toledo Teixeira
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Pierina Lorencini Parise
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Matheus Cavalheiro Martini
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Rafael Elias Marques
    Affiliations
    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Helison R. Carmo
    Affiliations
    Department of Clinical Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Alexandre Borin
    Affiliations
    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Laís Durço Coimbra
    Affiliations
    Brazilian Biosciences National Laboratory (LNBio), Campinas, SP, Brazil
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  • Vinícius O. Boldrini
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Natalia S. Brunetti
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Andre S. Vieira
    Affiliations
    Department of Animal Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
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  • Eli Mansour
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Raisa G. Ulaf
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Ana F. Bernardes
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Thyago A. Nunes
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Luciana C. Ribeiro
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Andre C. Palma
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Marcus V. Agrela
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Maria Luiza Moretti
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Andrei C. Sposito
    Affiliations
    Department of Clinical Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
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  • Fabrício Bíscaro Pereira
    Affiliations
    Hematology and Hemotherapy Center University of Campinas, Campinas, SP, Brazil
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  • Licio Augusto Velloso
    Affiliations
    Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, Brazil
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  • Marco Aurélio Ramirez Vinolo
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • André Damasio
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • José Luiz Proença-Módena
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, Brazil
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  • Robson Francisco Carvalho
    Affiliations
    Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, SP, Brazil
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  • Marcelo A. Mori
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • Daniel Martins-de-Souza
    Affiliations
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, BrazilD’Or Institute for Research and Education (IDOR), SP, BrazilInstituto Nacional de Biomarcadores em Neuropsiquiatria, Conselho Nacional de Desenvolvimento Científico e Tecnológico, SP, Brazil
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  • Helder I. Nakaya
    Affiliations
    Department of Clinical and Toxicological analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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  • Alessandro S. Farias
    Affiliations
    Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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  • Pedro Manoel M. Moraes-Vieira
    Correspondence
    Corresponding Author and Lead Contact: Prof. Pedro Manoel Mendes Moraes Vieira. Rua Monteiro Lobato, 255, Bl H, Instituto de Biologia, Universidade de Campinas, Campinas, Brazil, 13083-862.
    Affiliations
    Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, SP, BrazilObesity and Comorbidities Research Center (OCRC), University of Campinas, SP, BrazilExperimental Medicine Research Cluster (EMRC), University of Campinas, SP, Brazil
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    • Highlights

    • ●
      Elevated glucose levels regulate viral replication and cytokine production in monocytes
    • ●
      Glycolysis sustains CoV-2-induced monocyte response and viral replication
    • ●
      mtROS/HIF-1α is necessary for CoV-2 replication and monocyte cytokine production
    • ●
      Monocyte-derived cytokines drive T cell dysfunction and lung epithelial death.

    Summary

    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/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.
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