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1.
J Lipid Res ; 62: 100129, 2021.
Article in English | MEDLINE | ID: covidwho-1440205

ABSTRACT

The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Furthermore, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here, we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Furthermore, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for severe acute respiratory syndrome coronavirus 2.


Subject(s)
COVID-19/immunology , Cell Membrane/immunology , Eicosanoids/immunology , SARS-CoV-2/physiology , Sphingolipids/immunology , Virus Replication/immunology , Humans
2.
Int J Mol Sci ; 22(19)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438628

ABSTRACT

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient's outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution.


Subject(s)
COVID-19/blood , Sphingolipids/blood , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Female , Humans , Lipidomics , Male , Middle Aged , Prognosis , SARS-CoV-2/isolation & purification , Severity of Illness Index , Sphingolipids/analysis , Sphingomyelins/analysis , Sphingomyelins/blood , Young Adult
3.
Int J Mol Sci ; 22(11)2021 May 26.
Article in English | MEDLINE | ID: covidwho-1256559

ABSTRACT

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.


Subject(s)
Ceramides/metabolism , HIV-1/metabolism , Influenza A virus/metabolism , SARS-CoV-2/metabolism , Virus Diseases/metabolism , Virus Diseases/virology , Apoptosis/drug effects , Apoptosis/immunology , Ceramides/chemistry , Gene Expression Regulation, Viral , HIV-1/pathogenicity , Humans , Immunomodulation , Influenza A virus/pathogenicity , SARS-CoV-2/pathogenicity , Virion/growth & development , Virus Diseases/immunology , Virus Internalization , Virus Replication/drug effects , Virus Replication/immunology
4.
Cells ; 10(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1223958

ABSTRACT

Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.


Subject(s)
Bacterial Infections/immunology , Mycoses/immunology , Signal Transduction/immunology , Sphingosine/metabolism , Virus Diseases/immunology , Animals , Bacterial Infections/drug therapy , Bacterial Infections/metabolism , Bacterial Infections/microbiology , Cell Wall/drug effects , Ceramides/metabolism , Disease Models, Animal , Herpesvirus 1, Human/immunology , Humans , Lysophospholipids/metabolism , Membrane Microdomains/immunology , Membrane Microdomains/metabolism , Mycoses/drug therapy , Mycoses/metabolism , Mycoses/microbiology , SARS-CoV-2/immunology , Sphingolipids/metabolism , Sphingosine/analogs & derivatives , Sphingosine/pharmacology , Sphingosine/therapeutic use , Virus Diseases/drug therapy , Virus Diseases/metabolism , Virus Diseases/virology
5.
J Biol Chem ; 296: 100470, 2021.
Article in English | MEDLINE | ID: covidwho-1101336

ABSTRACT

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Dioxanes/pharmacology , Glucosyltransferases/antagonists & inhibitors , Glycosphingolipids/antagonists & inhibitors , Influenza A Virus, H1N1 Subtype/drug effects , Pyrrolidines/pharmacology , Quinuclidines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Carbamates/chemical synthesis , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/virology , Chlorocebus aethiops , Clinical Trials, Phase III as Topic , Dioxanes/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gene Expression Regulation , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Glycosphingolipids/biosynthesis , Host-Pathogen Interactions/genetics , Humans , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/drug therapy , Influenza, Human/enzymology , Influenza, Human/virology , Madin Darby Canine Kidney Cells , Pyrrolidines/chemical synthesis , Quinuclidines/chemical synthesis , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Vero Cells , Virus Replication/drug effects
6.
Prostaglandins Other Lipid Mediat ; 152: 106504, 2021 02.
Article in English | MEDLINE | ID: covidwho-899425

ABSTRACT

Sphingolipids are potent bioactive agents involved in the pathogenesis of various respiratory bacterial infections. To date, several sphingolipid derivatives are known, but S1P (Sphingosine-1-phosphate) and Ceramide are the best-studied sphingolipid derivatives in the context of human diseases. These are membrane-bound lipids that influence host-pathogen interactions. Based on these features, we believe that sphingolipids might control SARS-CoV-2 infection in the host. SARS-CoV-2 utilizes the ACE-II receptor (Angiotensin-converting enzyme II receptor) on epithelial cells for its entry and replication. Activation of the ACE-II receptor is indirectly associated with the activation of S1P Receptor 1 signaling which is associated with IL-6 driven fibrosis. This is expected to promote pathological responses during SARS-CoV-2 infection in COVID-19 cases. Given this, mitigating S1P signaling by application of either S1P Lyase (SPL) or S1P analog (Fingolimod / FTY720) seems to be potential approach for controlling these pathological outcomes. However, due to the immunosuppressive nature of FTY720, it can modulate hyper-inflammatory responses and only provide symptomatic relief, which may not be sufficient for controlling the novel COVID-19 infection. Since Th1 effector immune responses are essential for the clearance of infection, we believe that other sphingolipid derivatives like Cermaide-1 Phosphate with antiviral potential and adjuvant immune potential can potentially control SARS-CoV-2 infection in the host by its ability in enhancing autophagy and antigen presentation by DC to promote T cell response which can be helpful in controlling SARS-CoV-2 infection in novel COVID-19 patients.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19/drug therapy , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sphingolipids/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/pathology , Humans
7.
Metabolites ; 10(9)2020 Aug 31.
Article in English | MEDLINE | ID: covidwho-745182

ABSTRACT

The pathogenic mechanisms underlying the Biology and Biochemistry of viral infections are known to depend on the lipid metabolism of infected cells. From a lipidomics viewpoint, there are a variety of mechanisms involving virus infection that encompass virus entry, the disturbance of host cell lipid metabolism, and the role played by diverse lipids in regard to the infection effectiveness. All these aspects have currently been tackled separately as independent issues and focused on the function of proteins. Here, we review the role of cholesterol and other lipids in ssRNA+ infection.

8.
Med Hypotheses ; 143: 110127, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-663015

ABSTRACT

Fenofibrate, which is a PPAR-alfpha agonist, increases the level of sulfatide. In this letter we hypothesize on the background of various findings that this is beneficial against COVID-19. Fenofibrate has been used for decades against hypercholesterolemia and has no serious side effects. Therefore, a trial giving fenofibrate to patients with corona virus infection is recommended.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Fenofibrate/pharmacology , Hypolipidemic Agents/pharmacology , Pandemics , Pneumonia, Viral/drug therapy , Sulfoglycosphingolipids/blood , Adult , Aging/blood , COVID-19 , Child , Drug Repositioning , Fenofibrate/therapeutic use , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/complications , Hypertension/blood , Hypertension/complications , Hypolipidemic Agents/therapeutic use , PPAR alpha/antagonists & inhibitors , SARS-CoV-2 , Virus Internalization
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