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

Dias, Suelen da Silva Gomes; Soares, Vinícius Cardoso; Ferreira, André C.; Sacramento, Carolina Q; Fintelman-Rodrigues, Natália; Temerozo, Jairo R.; Teixeira, Lívia; Barreto, Ester A.; Mattos, Mayara; Freitas, Caroline de; Azevedo-Quintanilha, Isaclaudia G. de; Manso, Pedro Paulo de Abreu; Hottz, Eugênio D.; Pão, Camila R. R.; Bou‐Habib, Dumith Chequer; Bozza, Fernando A.; Souza, Thiago Moreno L.; Bozza, Patrı́cia T.

doi:10.1101/2020.08.22.262733

Cited by 16 publications

(17 citation statements)

References 50 publications

(65 reference statements)

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“…First, we report here that monocytes treated with recombinant spike protein subunit 1 from the current pandemic SARS-CoV-2 undergo a dose-dependent increase in glycolysis which is controlled by HIF-1α and mediates the production of pro-inflammatory cytokines. These data suggest an initial signaling event which precipitates changes in glucose and lipid metabolism during SARS-CoV-2 infection in monocytes which have been previously reported to be linked to inflammatory activation 34,35 . Monocyte and monocyte-derived macrophages are substantially enriched in the lungs of SARS-CoV-2-infected individuals with severe COVID-19 8,9,12–15 and respond to experimental viral infection by producing pro-inflammatory cytokines 34–38 , therefore these results reflect a potential mechanism by which hypercytokinemia occurs during the early innate immune response to SARS-CoV-2.…”

Section: Discussionsupporting

confidence: 60%

“…Recently it was demonstrated that SARS-CoV-2 promotes metabolic reprogramming in monocytes during infection 34,35 . Research in SARS-CoV suggested that the viral spike protein induces inflammatory responses in macrophages 40,41 , and this has recently been replicated using spike protein from SARS-CoV-2 42,43 .…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Codo et al . demonstrated pro-inflammatory glycolytic reprogramming in monocytes infected with SARS-CoV-2 34 , and SARS-CoV-2 also appears to alter monocyte lipid metabolism to promote lipid droplet formation which is associated with pro-inflammatory cytokine production 35 .…”

Section: Introductionmentioning

confidence: 99%

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

Cory

Emmons

Yarbro

et al. 2021

Preprint

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A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, 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 in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. 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 in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. 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.

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

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

Cory

Emmons

Yarbro

et al. 2021

Preprint

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“…Specifically, it was reported that HMG-CoA reductase is necessary to produce lipid droplets (LD) [39]. These cell organelles have been recently proposed as hubs for SARS-CoV-2 genome replication and viral particle assembly [40, 41]. According to the above, ATV treatment could affect the replication and assembly stages of SARS-CoV-2 by blocking LD production.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2in vitro

Flórez-Álvarez

Zapata

et al. 2021

Preprint

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Introduction: SARS-CoV-2 has caused a pandemic of historic proportions and continues to spread worldwide. Currently, there is no effective therapy against this virus. This article evaluated the in vitro antiviral effect of Atorvastatin against SARS-CoV-2 and also identified the interaction affinity between Atorvastatin and three SARS-CoV-2 proteins, using in silico structure-based molecular docking approach. Materials and methods: The antiviral activity of Atorvastatin against SARS-CoV-2 was evaluated by three different treatment strategies using a clinical isolate of SARS-CoV-2. The interaction of Atorvastatin with Spike, RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) was evaluated by molecular docking. Results: Atorvastatin showed anti-SARS-CoV-2 activity of 79%, 54.8%, 22.6% and 25% at 31.2, 15.6, 7.9, and 3.9 µM, respectively, by pre-post-treatment strategy. In addition, atorvastatin demonstrated an antiviral effect of 26.9% at 31.2 µM by pre-infection treatment. This compound also inhibited SARS-CoV-2 in 66.9%, 75%, 27.9% and 29.2% at concentrations of 31.2, 15.6, 7.9, and 3.9 µM, respectively, by post-infection treatment. The interaction of atorvastatin with SARS-CoV-2 Spike, RdRp and 3CL protease yielded a binding affinity of -8.5 Kcal/mol, -6.2 Kcal/mol, and -7.5 Kcal/mol, respectively. Conclusion: Our study demonstrated the in vitro anti-SARS-CoV-2 activity of Atorvastatin, mainly against the late steps of the viral replicative cycle. A favorable binding affinity with viral proteins by bioinformatics methods was also shown. Due to its low cost, availability, well-established safety and tolerability, and the extensive clinical experience of atorvastatin, it could prove valuable in reducing morbidity and mortality from COVID-19.

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“…The interaction of viral protein associated with proteins linked with LDs has also been studied in numerous positive-strand RNA viruses (Cheung et al 2010;Coffey et al 2006;Filipe and McLauchlan 2015;Lyn et al 2013;Samsa et al 2009;Villareal et al 2015). More recently, LDs accumulation increased in SARS-CoV2 patients, which act as fuel for SARS-CoV2 replication and consider as drug candidates to cure this pandemic virus (da Silva Gomes Dias et al 2020). LD also regulates intracellular bacteria-fighting machines and acts as a regulative role in innate immunity in mammalian cells (Bosch et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Impact of regulative noise exposure to biodiesel production due to enhanced lipid droplet production inSaccharomyces cerevisiae: Preliminary results from a laboratory experiment

Kumar

2020

Preprint

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Lipid Droplet (LD) is a ubiquitous cellular organelle that stores natural lipids as an energy and carbon source. It has emerged as a highly active organelle, engaged in lipid synthesis, protein storage, protein degradation, transportation, and metabolism. It stores natural lipids in the form of triacylglycerols (TAG) and steryl esters. TAGs consider promising biotechnological importance to produce biodiesel; thus, LD is considered a tremendous scientific concern in the modern era. As such, the LD assembly through microorganisms becomes an evident alternative against animal and plant-derived sources for economic reasons. Among microorganisms, the Saccharomyces cerevisiae is a better alternative for industrial utilization but has low production of TAGs. Thus, to enhance the LD concentration, novel research was designed to induce alternate high and low sound frequency at a regular interval on a yeast model organism. The control and treated yeast samples further investigated using biochemical, biophysical, and computational tools to conclude that cells increase lipid droplet production under noise exposure. Further, it regulates cell proliferation and maintains the ROS level; hence, persistent noise exposure acts as an inducer of LD accumulation with maintaining cell toxicity. The results endorsed that noise induces yeast LD yield is significantly higher than control, which could be considered a milestone in the biodiesel industry development and the biodiesel policy. This analysis also assists researchers in the understanding of the novel function of LDs.Abstract Figure

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

Cited by 16 publications

References 50 publications

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

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

Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2in vitro

Impact of regulative noise exposure to biodiesel production due to enhanced lipid droplet production inSaccharomyces cerevisiae: Preliminary results from a laboratory experiment

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