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

Codo, Ana Campos; Davanzo, Gustavo Gastão; Monteiro, Lauar de Brito; Souza, Gabriela Fabiano de; Muraro, Stéfanie Primon; Virgílio-da-Silva, João Victor; Prodonoff, Juliana Silveira; Carregari, Victor Corasolla; Biagi, Carlos Alberto Oliveira de; Crunfli, Fernanda; Restrepo, Jeffersson Leandro Jimenez; 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 Rafael Pereira do; Borin, Alexandre; Coimbra, Laís D.; Boldrini, Vinícius O.; Brunetti, Natália S; Vieira, André Schwambach; Mansour, Eli; Ulaf, Raisa G.; Bernardes, Ana Flávia; Nunes, Thyago A.; Ribeiro, Luciana C.; Palma, André C.; Agrela, Marcus Vinicius Rodrigues de; Moretti, Maria Luíza; Sposito, Andrei C.; Pereira, Fabrício Ramos Silvestre; Velloso, Lı́cio A.; Vinolo, Marco Aurélio Ramirez; Damásio, 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.

doi:10.1016/j.cmet.2020.07.007

Cited by 676 publications

(766 citation statements)

References 38 publications

Supporting

Mentioning

686

Contrasting

Unclassified

Order By: Relevance

“…Human monocytes infected with SARS-CoV-2 were shown to sustain genome viral replication, express higher level of pro-inflammatory cytokine and may undergo cell death (Codo et al, 2020). To gain insights on the functions of LDs in SARS-CoV-2 infection, LD biogenesis was inhibited by A922500, DGAT-1 inhibitor.…”

Section: Sars-cov-2 Infected Monocytesmentioning

confidence: 99%

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Dias

Soares

Ferreira

et al. 2020

Preprint

View full text Add to dashboard Cite

Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs, identifying the host pathways essential for the virus replication may lead to potential targets for therapeutic intervention. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are not fully known. Lipid droplets (LD) are organelles with major functions in lipid metabolism and energy homeostasis, and have multiple roles in infections and inflammation. Here we demonstrate that monocytes from COVID-19 patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection modulates pathways of lipid synthesis and uptake, as CD36, SREBP-1, PPARγ and DGAT-1 in human monocytes and triggered LD formation in different human cells. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA. The pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of pro-inflammatory mediators. Taken together, we demonstrate the essential role of lipid metabolic reprograming and LD formation in SARS-CoV-2 replication and pathogenesis, opening new opportunities for therapeutic strategies to COVID-19.

show abstract

Section: Sars-cov-2 Infected Monocytesmentioning

confidence: 99%

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Dias

Soares

Ferreira

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, better understanding the driving causes of cytokine storm and identifying potential multicytokine blockers are still urgent need. Considering the previously reported high correlation between metabolism and immune response 13,17,27,35 , and the key role of metabolism in regulating cytokine release upon viral infection 16,22 , we speculated that the metabolism and CRS may correlate well and correcting the dysregulated host metabolism may suppress the SARS-CoV-2-induced CRS. We thus characterized the metabolic and immune profiling in the same COVID-19 patient cohort, and our network correlation analysis between circulating metabolite and cytokine levels revealed the potential regulatory role of arginine metabolism, tryptophan metabolism, and purine metabolism in proinflammatory responses.…”

Section: Discussionmentioning

confidence: 92%

“…αketoglutarate-supplemented diet has been reported to induce IL-10 production, thus leading to suppression of chronic inflammation and extension of life span 37 . Particularly, elevated glucose levels in COVID-19 patients promote SARS-CoV-2 replication and cytokine production in monocytes 16 . A very recent study suggests that the a high kynurenic acid to kynurenine ratio is linked to immune responses and clinical outcomes in male COVID-19 patients 38 .…”

Section: Discussionmentioning

confidence: 99%

“…The association of metabolism and immunity has been reported since 1960s 12 ，and many studies have shown that metabolic pathways can regulate the innate and adaptive host responses to the infection of various viruses, such as human immunodeficiency virus (HIV) 13 , yellow fever virus 14 , severe fever with thrombocytopenia syndrome virus (SFTSV) [15][16][17] . Since the COVID-19 pandemic, studies exploring the immunological and metabolic signatures in patients have been reported extensively 5,7,18,19 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Host metabolite-cytokine correlation landscape in SARS-CoV-2 infection

Xiao

Nie

Pang

et al. 2020

Preprint

View full text Add to dashboard Cite

The systemic cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. It has been well-known that metabolism plays a role in modulating the immune responses in infectious diseases. Yet, how the host metabolism correlates with CRS in COVID-19 patients and how the perturbed metabolites affect the cytokine release remains unclear. Here, we performed both metabolomics and cytokine/chemokine profiling on serum samples from the same cohort of healthy controls, mild and severe COVID-19 patients and delineated the global metabolic and immune response landscape along disease progression. Intriguingly, the correlation analysis revealed the tight link between metabolites and proinflammatory cytokines and chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, implying the potential regulatory role of arginine metabolism, tryptophan metabolism, and purine metabolism in hyperinflammation. Importantly, we demonstrated that targeting metabolism markedly modulated the proinflammatory cytokines release by PBMCs isolated from SARS-CoV-2-infected rhesus macaques ex vivo. Beyond providing a comprehensive resource of metabolism and immunology data of SARS-CoV-2 infection, our study showed that metabolic alterations can be potentially exploited to develop novel strategy for the treatment of fatal CRS in COVID-19.

show abstract

“…There is increasing evidence that SARS-CoV-2 infection activates the NLRP3 inflammasome (Siu et al, 2019) with increased levels of IL-18 and lactate dehydrogenase (LDH) levels due to inflammasome mediated pyroptotic cell death (Lucas et al, 2020;Zhou et al, 2020). It is now known that increased glycolysis, which activates inflammasome is associated with worsened COVID-19 outcome (Codo et al, 2020). This raises the question whether the substrate switch from glycolysis-to-ketogenesis, can be employed to stave off COVID-19 in high risk elderly population.…”

Section: Introductionmentioning

confidence: 99%

Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model

Ryu

Shchukina²,

Youm

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYIncreasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective γδ T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly.Highlights-Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.-Aged infected mice have systemic inflammation and inflammasome activation-Murine beta coronavirus (mCoV) infection results in loss of pulmonary γδ T cells.-Ketones protect aged mice from infection by reducing inflammation.eTOC BlurbElderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of γδ T cells that was corrected by ketogenic diet.

show abstract

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

Cited by 676 publications

References 38 publications

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Host metabolite-cytokine correlation landscape in SARS-CoV-2 infection

Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model

Contact Info

Product

Resources

About