Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

Barberis, Elettra; Timo, Sara; Amede, Elia; Vanella, Virginia Vita; Puricelli, Chiara; Cappellano, Giuseppe; Raineri, Davide; Cittone, Micol Giulia; Rizzi, Eleonora; Pedrinelli, Anita; Vassia, Veronica; Casciaro, Giuseppe Francesco; Priora, Simona; Nerici, Ilaria; Galbiati, Alessandra; Hayden, Eyal; Falasca, Marco; Vaschetto, Rosanna; Sainaghi, Pier Paolo; Dianzani, Umberto; Rolla, Roberta; Chiocchetti, Annalisa; Baldanzi, Gianluca; Marengo, Emílio; Manfredi, Marcello

doi:10.3390/ijms21228623

Cited by 206 publications

(252 citation statements)

References 68 publications

(65 reference statements)

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“…Fatty acid synthesis was reported to increase in SARS-CoV-2 infection ( Ehrlich et al 2020 ), whereas our results suggest a more complex pattern for different fatty acid species ( Fig. 2H ), which echoes the results of several metabolomics studies ( Shen et al 2020 , Barberis et al 2020 , Thomas et al 2020 ). Both TCA cycle and OXPHOS have been shown to decrease based on gene expression during the virus infection ( Ehrlich et al 2020 , Gardinassi et al 2020 ), and have been implicated in the systemic syndromes of the virus ( Li et al 2020 ).…”

Section: Discussionsupporting

confidence: 88%

Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets

Cheng

Martin-Sancho

Pal

et al. 2021

Preprint

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Tremendous progress has been made to control the COVID-19 pandemic, including the development and approval of vaccines as well as the drug remdesivir, which inhibits the SARS-CoV-2 virus that causes COVID-19. However, remdesivir confers only mild benefits to a subset of patients, and additional effective therapeutic options are needed. Drug repurposing and drug combinations may represent practical strategies to address these urgent unmet medical needs. Viruses, including coronaviruses, are known to hijack the host metabolism to facilitate their own proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM). We find that SARS-CoV-2 infection can induce recurrent and complicated metabolic reprogramming spanning a wide range of metabolic pathways. We next applied the GEM-based metabolic transformation algorithm (MTA) to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. These predictions are enriched for validated targets from various published experimental drug and genetic screens. Further analyzing the RNA-sequencing data of remdesivir-treated Vero E6 cell samples that we generated, we predicted metabolic targets that act in combination with remdesivir. These predictions are enriched for previously reported synergistic drugs with remdesivir. Since our predictions are based in part on human patient data, they are likely to be clinically relevant. We provide our top high-confidence candidate targets for their evaluation in further studies, demonstrating host metabolism-targeting as a promising antiviral strategy.

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Section: Discussionsupporting

confidence: 88%

Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets

Cheng

Martin-Sancho

Pal

et al. 2021

Preprint

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“…The involvement of LMs was reported by Barberis et al [ 144 ]. The authors performed untargeted lipidomics and metabolomics analyses on plasma samples of 161 subjects, 103 of whom were infected with SARS-CoV-2.…”

Section: Dysregulation Of Lipids In Covid-19 Diseasementioning

confidence: 71%

“…The bio-fluid analysed, the number of samples, the platform used and the main altered lipid species are shown. Bio-fluid N. of samples Platform Main altered lipids Reference Serum 108 High-Res MS Glycerophospholipids Shen et al [ 136 ] Serum 50 QQQ GM3s, free fatty acids Song et al [ 137 ] Plasma 35 QQQ NEFAs, TAGs, PCs Wu et al [ 148 ] Serum 57 QQQ PUFAs and lipid mediators Schwarz et al [ 141 ] Plasma 161 High-Res MS PCs, LPCs, PEs, LPEs, NEFAs Barberis et al [ 144 ] Serum 49 High-Res MS Acylcarnitines, NEFAs Thomas et al [ 138 ] Serum 236 NMR Short chain fatty acids Bruzzone et al [ 146 ] Plasma 102 High-Res MS and QQQ TAGs, PCs Overmyer et al [ 145 ] …”

Section: Dysregulation Of Lipids In Covid-19 Diseasementioning

confidence: 99%

“…Wu et al generated ROC curves of modulated lipids for discriminating between patients with COVID-19 and healthy controls, indicating glycerol 3-phosphate as the best biomarker, with an AUC value of 1.00 [ 152 ]. Finally, Barberis and co-authors reported that molecular species 14:0/22:6-PC, 16:1/22:6-PC, and 18:1/20:4-PE were promising potential biomarkers, with an area under the curve (AUC) values of 0.96, 0.97, and 0.94, respectively, whilst their integrated ROC reported an AUC of 0.97 [ 144 ]. The best biomarkers were arachidonic acid (FA 20:4), oleic acid (FA 18:1), 18:2/20:4-PE, and 16:1/18:2-PE, with AUC values of 0.99, 0.98 0.92, and 0.92, respectively.…”

Section: Lipids As Biomarkers Of Sars-cov-2 Infectionmentioning

confidence: 99%

“…The authors also suggested the use of drugs inhibiting lipid syntheses such as statins, which had already been proposed to treat HCV [ 153 ] and COVID-19 [ 154 ]. On the other hands, Barberis et al identified a down-regulation of glycerophospholipids and an up-regulation of LPLs, arachidonic acid and oleic acid, suggesting a strong involvement of PLA2 in the pathogenesis and progression of COVID-19 [ 144 ]. The involvement of PLA2 is also supported by Thomas et al that found increased amounts of long-chain PUFAs, that are particularly enriched in the sn-2 position of phospholipids.…”

Section: Lipids and Lipids Metabolisms As Potential Therapeutic Targementioning

confidence: 99%

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Dissecting lipid metabolism alterations in SARS-CoV-2

Casari

Manfredi

Metharom

et al. 2021

Progress in Lipid Research

Self Cite

101

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that has infected over sixteen million people globally. There have been more than two million deaths recorded worldwide, with no end in sight until a vaccine is developed. Current research has centred on different aspects of the virus interaction with cell surface receptors, but more needs to be done to further understand its mechanism of action in order to develop a targeted therapy and a method to control the spread of the virus. Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid signalling and synthesis to affect host cell lipidome. Emerging studies using untargeted metabolomic and lipidomic approaches are providing new insight into the host response to COVID-19 infection. Indeed, metabolomic and lipidomic approaches have identified numerous circulating lipids that directly correlate to the severity of the disease, making lipid metabolism a potential therapeutic target. Circulating lipids play a key function in the pathogenesis of the virus and exert an inflammatory response. A better knowledge of lipid metabolism in the host-pathogen interaction will provide valuable insights into viral pathogenesis and to develop novel therapeutic targets.

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Is there an interplay between the SARS‐CoV‐2 spike protein and Platelet‐Activating factor?

et al. 2022

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Previous publications have reported a potent effect of COVID‐19 on platelet function and that the Spike protein enhances washed human platelet aggregation induced by various agonists. This study aims to evaluate whether mRNA vaccination for COVID‐19 affects human platelet‐rich plasma (hPRP) aggregation response, whether a recombinant Spike protein modulates PAF‐induced aggregation in hPRP and in washed rabbit platelets (WRP), and to investigate the effect of recombinant Spike protein on the PAF production in the U‐937 cell line. Our results showed that PRP from vaccinated individuals exhibited ex vivo lower EC50 values in response to PAF, ADP, and collagen. Platelet incubation with the Spike protein alone did not induce aggregation either in hPRP or in WRP, but resulted in augmentation of in vitro PAF‐induced aggregation in hPRP from non‐vaccinated individuals and in WRP. When PRP from vaccinated individuals was incubated with the Spike protein and PAF was subsequently added, elimination of the secondary wave of the biphasic aggregation curve was recorded compared with the aggregation induced by PAF alone. Collagen‐induced in vitro aggregation was dose‐dependently reduced when platelets were pre‐incubated with the Spike protein in all tested aggregation experiments. Stimulation of U‐937 by the Spike protein induced an increase in intracellular PAF production accompanied by elevation of the activities of all three PAF biosynthetic enzymes. In conclusion, since the Spike protein appears to modulate PAF production and activity, the use of compounds that act as PAF inhibitors, could be considered at least in mild cases of patients infected with SARS‐CoV‐2.

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Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

Cited by 206 publications

References 68 publications

Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets

Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets

Dissecting lipid metabolism alterations in SARS-CoV-2

Is there an interplay between the SARS‐CoV‐2 spike protein and Platelet‐Activating factor?

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