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1.
Life Sci Alliance ; 5(1)2022 01.
Article in English | MEDLINE | ID: covidwho-1515726

ABSTRACT

Understanding pathways that might impact coronavirus disease 2019 (COVID-19) manifestations and disease outcomes is necessary for better disease management and for therapeutic development. Here, we analyzed alterations in sphingolipid (SL) levels upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection induced elevation of SL levels in both cells and sera of infected mice. A significant increase in glycosphingolipid levels was induced early post SARS-CoV-2 infection, which was essential for viral replication. This elevation could be reversed by treatment with glucosylceramide synthase inhibitors. Levels of sphinganine, sphingosine, GA1, and GM3 were significantly increased in both cells and the murine model upon SARS-CoV-2 infection. The potential involvement of SLs in COVID-19 pathology is discussed.


Subject(s)
COVID-19/metabolism , Disease Models, Animal , Sphingolipids/metabolism , Virus Replication/physiology , Animals , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Chromatography, Liquid/methods , Dioxanes/pharmacology , Gangliosides/blood , Gangliosides/metabolism , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Humans , Mass Spectrometry/methods , Mice, Transgenic , Pyrrolidines/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sphingolipids/blood , Sphingosine/analogs & derivatives , Sphingosine/blood , Sphingosine/metabolism , Vero Cells , Virus Replication/drug effects
2.
Cells ; 10(9)2021 08 24.
Article in English | MEDLINE | ID: covidwho-1376745

ABSTRACT

As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.


Subject(s)
Sphingolipids/metabolism , Virus Diseases , Biological Transport , Cell Membrane/chemistry , Ceramides/metabolism , Drug Delivery Systems , HIV/growth & development , Host Microbial Interactions , Intracellular Membranes/chemistry , SARS-CoV-2/growth & development , Virion , Virus Replication , Viruses/growth & development
3.
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
4.
STAR Protoc ; 2(1): 100356, 2021 03 19.
Article in English | MEDLINE | ID: covidwho-1062653

ABSTRACT

This protocol enables the testing of drugs against infection of epithelial cells with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), using pseudo-typed replication deficient vesicular stomatitis virus particles (pp-VSV) presenting the SARS-CoV-2 spike protein. After treating human volunteers with amitriptyline, an approved antidepressant and inhibitor of the acid sphingomyelinase, freshly isolated nasal epithelial cells were infected ex vivo and infection levels were quantified. This protocol offers the possibility to rapidly test the efficacy of potential drugs in the fight against COVID-19. For complete details on the use and execution of this protocol, please refer to Carpinteiro et al. (2020).


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , Drug Evaluation, Preclinical/methods , SARS-CoV-2/drug effects , Sphingolipids/metabolism , Cell Culture Techniques , Cells, Cultured , Epithelial Cells/cytology , Humans , Nasal Mucosa/cytology , Spike Glycoprotein, Coronavirus , Vesicular stomatitis Indiana virus
5.
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
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