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The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium

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... One of the hallmarks in cancer is the Warburg effect, or aerobic glycolysis. It is well established in a variety of cancers [111] and recently identified in SARS-CoV-2-infected cells [112]. The widely-applied cancer detection method, the PET (positron emission tomography) scan, was developed based on the Warburg effect, and incidental detections of PET/CT positive SARS-CoV-2-infected lesions in cancer patients have been reported [113], indicating the increased glycolysis in infected cells. ...
... Warburg effect Increased aerobic glycolysis in vitro [112], incidental detection of PET/CT positive infected lesions in cancer patients [113] Well established in a variety of cancers [111] PAI-1 Increased in the plasma [5,6] PAI-1 increase in the plasma and tissue of various type of human cancers [191] Hyaluronan Significant increase in the serum of critical cases [22,184], prominent hyaluronan exudates in the COVID-19 lungs [20,21] Increase in the serum of advanced cancers [192], the degree of HA accumulation is strongly correlated with a poor prognosis in advanced cancer patients [193] Tregs FoxP3 + Tregs with tumor-infiltration Treg signature [43] High FoxP3 + Tregs infiltration was significantly associated with shorter overall survival in the majority of solid tumors [194] EGFR Activated EGFR in mouse model of SARS-CoV-1 [195], in vitro model of SARS-CoV-2 [150] A driver of tumorigenesis mostly in lung and breast cancer and in glioblastoma [196] T. Matsuyama et al. supplementation also resulted in higher levels of glucagon-like peptide-1 (GLP-1), a gut hormone known to increase insulin levels [120]. Prophylactic glutamine supplementation is recommended to those in high-risk groups; however, glutamine supplementation after the infection should be carefully considered. ...
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SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD⁺, coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3⁺ Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.
... Coronaviruses including MERS-CoV rearrange cellular lipid profiles upon infection (Yan et al, 2019a;Yuan et al, 2019b). Recent studies have reported that SARS-CoV-2 also induces changes in numerous metabolic pathways including TCA cycle, oxidative phosphorylation, and lipid metabolism among others in human patient samples (preprint: Ehrlich et al, 2020;Gardinassi et al, 2020). Notably, counteracting the metabolic demands of viruses including MERS-CoV has been shown to abolish their ability to infect the host cells (Mayer et al, 2019;Yuan et al, 2019), and the PPARa-agonist fenofibrate can reverse some of the SARS-CoV-2induced metabolic changes and reduce the viral load (preprint: Ehrlich et al, 2020). ...
... Recent studies have reported that SARS-CoV-2 also induces changes in numerous metabolic pathways including TCA cycle, oxidative phosphorylation, and lipid metabolism among others in human patient samples (preprint: Ehrlich et al, 2020;Gardinassi et al, 2020). Notably, counteracting the metabolic demands of viruses including MERS-CoV has been shown to abolish their ability to infect the host cells (Mayer et al, 2019;Yuan et al, 2019), and the PPARa-agonist fenofibrate can reverse some of the SARS-CoV-2induced metabolic changes and reduce the viral load (preprint: Ehrlich et al, 2020). Therefore, targeting the virus-induced metabolic changes can be a promising novel antiviral strategy (Mayer et al, 2019), and can be especially valuable in anti-SARS-CoV-2 drug repurposing to address the current urgent COVID-19 crisis considering that many existing drugs are metabolism-targeting. ...
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Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral 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), revealing complicated host metabolism reprogramming during SARS-CoV-2 infection. We next applied the GEM-based metabolic transformation algorithm to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco-2 cells. Further generating and analyzing RNA-sequencing data of remdesivir-treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti-SARS-CoV-2 drug. Our study provides clinical data-supported candidate anti-SARS-CoV-2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.
... The topic of viral infection onset is currently very important due to its relationship with the ongoing COVID-19 pandemic. A study performed on primary human bronchial epithelial cells infected with SARS-CoV-2 revealed severe alterations in the gene transcription pattern that manifested endoplasmic reticular and mitochondrial stress, metabolic reprogramming toward intensive lipid synthesis and accumulation, impaired fatty-acid oxidation, and upregulated aerobic glycolysis via activation of the NF-κB pathway [125]. Such a metabolic signature suggests that infection impairs PPARα signaling. ...
... Therefore, the restoration of PPARα activity could be beneficial through reversal of these changes and metabolic 'repair'. Indeed, the treatment of the infected cell cultures with PPARα ligand fenofibrate alleviated the dysregulation of lipid metabolism, blocked infection-induced phospholipid accumulation, and remarkably decreased viral load by 100-fold within 3 days and 1000-fold within 5 days [125]. These results seem to support the hypothesis that fenofibrate treatment could alleviate the acute infection symptoms during COVID-19 by supporting fatty-acid metabolism in alveolar epithelial cells, improving pulmonary endothelial cell function, and calming down the cytokine storm, leading to a better outcome for the patients [126]. ...
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Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various inflammatory reactions. In this review, we focus on its role in the regulation of innate immunity; in particular, we discuss the PPARα interplay with inflammatory transcription factor signaling, pattern-recognition receptor signaling, and the endocannabinoid system. We also present examples of the PPARα-specific immunomodulatory functions during parasitic, bacterial, and viral infections, as well as approach several issues associated with innate immunity processes, such as the production of reactive nitrogen and oxygen species, phagocytosis, and the effector functions of macrophages, innate lymphoid cells, and mast cells. The described phenomena encourage the application of endogenous and pharmacological PPARα agonists to alleviate the disorders of immunological background and the development of new solutions that engage PPARα activation or suppression.
... The repression of PPAR-γ plays a key role in the induction of cytokine storm of inflammatory monocytes/macrophages in the SARS-CoV-2-infected lung. It has also been shown that SARS-CoV-2 modifies lipid metabolism in the lung epithelial cells by modulating the expression of PPARα, and thus contributes to lipotoxicity and respiratory problems [30]. Thus, downregulation of PPARs in COVID-19 may be considered as an important modulator of pulmonary inflammation and acute lung injury [31]. ...
... In this regard, the activation of PPARs may serve as an effective therapeutic strategy to decrease the inflammatory perturbations during SARS-CoV-2 infection. Recently, Ehrlich et al reported that the PPARα agonist, fenofibrate decreased the phospholipid accumulation in SARS-CoV-2 infected cells, and inhibited viral replication [30]. Fenofibrate inhibits the downregulation of PPARα activation caused by inflammation, decreases cytokine production by LPS or TNFα [32,33], and improves fatty acid oxidation, thus averting acute lung injury [31]. ...
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SARS-CoV-2 requires serine protease, transmembrane serine protease 2 (TMPRSS2), and cysteine proteases, cathepsins B, L (CTSB/L) for entry into host cells. These host proteases activate the spike protein and enable SARS-CoV-2 entry. We herein performed genomic-guided gene set enrichment analysis (GSEA) to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L. Further, medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 and CTSB/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Next, we analyzed drug-gene and gene-gene interaction networks using 809 human targets of SARS-CoV-2 proteins. The network results indicate that estradiol interacts with 370 (45%) and retinoic acid interacts with 251 (31%) human proteins. Interestingly, a combination of estradiol and retinoic acid interacts with 461 (56%) of human proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggests that both the drugs bind to TMPRSS2 and CTSL with the nanomolar to low micromolar affinity. The results suggest that these drugs can simultaneously target both the entry pathways of SARS-CoV-2 and thus can be considered as a potential treatment option for COVID-19.
... subjects, due to its reported cholesterol-lowering ability (A. C. Li & Glass, 2002;M. Zhang et al., 2016) similarly to fenofibrate, a cholesterol-lowering drug, which demonstrated promising effects against SARS-CoV-2 replication as well as pathogenesis (Ehrlich et al., 2020). ...
Article
The interim results of the large, multinational trials on coronavirus disease 2019 (COVID‐19) using a combination of antiviral drugs appear to have little to no effect on the 28‐day mortality or the in‐hospital course. Therefore, there is a still vivid interest in finding alternate re‐purposed drugs and nutrition supplements, which can halt or slow the disease severity. We review here the multiple preclinical studies, partially supported by clinical evidence showing the quercetin's possible therapeutic/prophylaxis efficacy against severe acute respiratory syndrome coronavirus (SARS‐CoV) as well as comorbidities like chronic obstructive pulmonary disease (COPD), diabetes mellitus, obesity, coagulopathy, and hypertension. Currently, 14 interventional clinical trials are underway assessing the efficacy of quercetin along with other antiviral drugs/nutritional supplements as prophylaxis/treatment option against COVID‐19. The present review is tempting to suggest that, based on circumstantial scientific evidence and preliminary clinical data, the flavonoid quercetin can ameliorate COVID‐19 infection and symptoms acting in concert on two parallel and independent paths: inhibiting key factors responsible for SARS‐CoV‐2 infections and mitigating the clinical manifestations of the disease in patients with comorbid conditions. Despite the broad therapeutic properties of quercetin, further high power randomized clinical trials are needed to firmly establish its clinical efficacy against COVID‐19.
... The glycolytic inhibitor, 2-Deoxy-D-glucose (2-DG), is a synthetic analog of glucose, which blocks glycolysis at the initial stage and causes depletion of ATP, anabolic intermediates required for virus synthesis, and glucose derivatives used in protein glycosylation [10]. It is demonstrated in earlier studies that inhibition of reprogrammed metabolism of virus-infected host cells using 2-DG potently impairs virus multiplication by reverting anabolic reprogramming [6][7][8][11][12][13][14]. Hence, we used 2-DG to target the selective and predominant metabolic pathway of the virus-infected host cell, glycolysis, to inhibit virus multiplication. ...
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Aims Virus-infected host cells switch their metabolism to a more glycolytic phenotype, required for new virion synthesis and packaging. Therefore, we investigated the effect and mechanistic action of glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) on virus multiplication in host cells following SARS-CoV-2 infection. Main methods SARS-CoV-2 induced change in glycolysis was examined in Vero E6 cells. Effect of 2-DG on virus multiplication was evaluated by RT-PCR (N and RdRp genes) analysis, protein expression analysis of Nucleocapsid (N) and Spike (S) proteins and visual indication of cytopathy effect (CPE), The mass spectrometry analysis was performed to examine the 2-DG induced change in glycosylation status of receptor binding domain (RBD) in SARS-CoV-2 spike protein. Key findings We observed SARS-COV-2 infection induced increased glucose influx and glycolysis, resulting in selectively high accumulation of the fluorescent glucose analog, 2-NBDG in Vero E6 cells. 2-DG inhibited glycolysis, reduced virus multiplication and alleviated cells from virus-induced cytopathic effect (CPE) in SARS-CoV-2 infected cells. The progeny virions produced from 2-DG treated cells were found unglycosylated at crucial N-glycosites (N331 and N343) of the receptor-binding domain (RBD) in the spike protein, resulting in production of defective progeny virions with compromised infective potential. Significance The mechanistic study revealed that the inhibition of SARS-COV-2 multiplication is attributed to 2-DG induced glycolysis inhibition and possibly un-glycosylation of the spike protein, also. Therefore, based on its previous human trials in different types of Cancer and Herpes patients, it could be a potential molecule to study in COVID-19 patients.
... For these reasons, the use of PPARα agonists may be a useful therapeutic strategy to reverse the inflammatory and metabolic changes induced by SARS-CoV-2 [64]. A recent study showed that the PPARα agonist fenofibrate reversed the metabolic changes caused by SARS-CoV-2 and inhibited the viral replication in lung epithelial cells [65]. Fenofibrate was found to inhibit the cytopathic effect exerted by SARS-CoV-2 on Vero E6 cells at 20 µM [66]. ...
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The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed.
... Fenofibrate decreases the expression of other cytokines (IL17, CCL2, and CCL20) implicated in COVID-19 pathology [41]. As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate prevents phospholipid accumulation within SARS-CoV-2 infected cells, blocking viral replication as well as pathogenesis by affecting the pathways of lipid metabolism in lung cells of COVID-19 patients [42]. It may also suppress microvascular inflammation and apoptosis through inhibition of nuclear factor-κB and activation of adenosine monophosphate (AMP)-activated protein kinase [43], suggesting the fenofibrate may further have favorable systemic anti-inflammatory and endothelial effects. ...
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Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.
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