Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1

A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immu...

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Autores principales:	Theodore J. Cory, Russell S. Emmons, Johnathan R. Yarbro, Kierstin L. Davis, Brandt D. Pence
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	COVID-19 SARS-CoV-2 immunometabolism inflammation monocyte Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/47fb14b898bc40a48c9df3860b4db0bf
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spelling	oai:doaj.org-article:47fb14b898bc40a48c9df3860b4db0bf2021-11-11T06:31:31ZMetformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 11664-322410.3389/fimmu.2021.733921https://doaj.org/article/47fb14b898bc40a48c9df3860b4db0bf2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.733921/fullhttps://doaj.org/toc/1664-3224A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.Theodore J. CoryRussell S. EmmonsJohnathan R. YarbroJohnathan R. YarbroKierstin L. DavisBrandt D. PenceBrandt D. PenceFrontiers Media S.A.articleCOVID-19SARS-CoV-2immunometabolisminflammationmonocyteImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 SARS-CoV-2 immunometabolism inflammation monocyte Immunologic diseases. Allergy RC581-607
spellingShingle	COVID-19 SARS-CoV-2 immunometabolism inflammation monocyte Immunologic diseases. Allergy RC581-607 Theodore J. Cory Russell S. Emmons Johnathan R. Yarbro Johnathan R. Yarbro Kierstin L. Davis Brandt D. Pence Brandt D. Pence Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
description	A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.
format	article
author	Theodore J. Cory Russell S. Emmons Johnathan R. Yarbro Johnathan R. Yarbro Kierstin L. Davis Brandt D. Pence Brandt D. Pence
author_facet	Theodore J. Cory Russell S. Emmons Johnathan R. Yarbro Johnathan R. Yarbro Kierstin L. Davis Brandt D. Pence Brandt D. Pence
author_sort	Theodore J. Cory
title	Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
title_short	Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
title_full	Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
title_fullStr	Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
title_full_unstemmed	Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1
title_sort	metformin suppresses monocyte immunometabolic activation by sars-cov-2 spike protein subunit 1
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/47fb14b898bc40a48c9df3860b4db0bf
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Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1

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