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

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 i...

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Published in:Cell Metabolism 2020-09, Vol.32 (3), p.437-446.e5
Main Authors: Codo, Ana Campos, Davanzo, Gustavo Gastão, Monteiro, Lauar de Brito, de Souza, Gabriela Fabiano, Muraro, Stéfanie Primon, Virgilio-da-Silva, João Victor, Prodonoff, Juliana Silveira, Carregari, Victor Corasolla, de Biagi Junior, Carlos Alberto Oliveira, Crunfli, Fernanda, Jimenez Restrepo, Jeffersson Leandro, Vendramini, Pedro Henrique, Reis-de-Oliveira, Guilherme, Bispo dos Santos, Karina, Toledo-Teixeira, Daniel A., Parise, Pierina Lorencini, Martini, Matheus Cavalheiro, Marques, Rafael Elias, Carmo, Helison R., Borin, Alexandre, Coimbra, Laís Durço, Boldrini, Vinícius O., Brunetti, Natalia S., Vieira, Andre S., Mansour, Eli, Ulaf, Raisa G., Bernardes, Ana F., Nunes, Thyago A., Ribeiro, Luciana C., Palma, Andre C., Agrela, Marcus V., Moretti, Maria Luiza, Sposito, Andrei C., Pereira, Fabrício Bíscaro, Velloso, Licio Augusto, Vinolo, Marco Aurélio Ramirez, Damasio, André, Proença-Módena, José Luiz, Carvalho, Robson Francisco, Mori, Marcelo A., Martins-de-Souza, Daniel, Nakaya, Helder I., Farias, Alessandro S., Moraes-Vieira, Pedro M.
Format: Article
Language:English
Subjects:
Adult
Betacoronavirus - physiology
Blood Glucose - metabolism
Cell Line
Coronavirus Infections - complications
Coronavirus Infections - metabolism
COVID-19
diabetes
Diabetes Complications - complications
Diabetes Complications - metabolism
Diabetes Mellitus - metabolism
Female
Glycolysis
HIF-1alpha
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
inflammation
Inflammation - complications
Inflammation - metabolism
interferon
Male
metabolism
Middle Aged
mitochondria
monocyte
Monocytes - metabolism
Monocytes - virology
Pandemics
Pneumonia, Viral - complications
Pneumonia, Viral - metabolism
Reactive Oxygen Species - metabolism
SARS-CoV-2
Short
Signal Transduction
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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 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. [Display omitted] •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 epithelial cell death Diabetic people with uncontrolled blood glucose levels have a greater risk to develop severe COVID-19 disease. Codo et al. show that elevated glucose levels and glycolysis promote SARS-CoV-2 (CoV-2) replication and cytokine production in monocytes through a mitochondrial ROS/hypoxia-inducible factor-1α dependent pathway, resulting in T cell dysfunction and epithelial cell death.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2020.07.007