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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Sphingolipids as Modulators of SARS-CoV-2 Infection
Kid Törnquist1,2, Muhammad Yasir Asghar1, Vignesh Srinivasan1,3
1Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic with severe consequences for afflicted individuals and the society as a whole. The biology and infectivity of the virus has been intensively studied in order to gain a better understanding of the molecular basis of virus-host cell interactions during infection. It is known that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) via its spike protein. Priming of the virus by specific proteases leads to viral entry via endocytosis and to the subsequent steps in the life cycle of SARS-CoV-2. Sphingosine and ceramide belong to the sphingolipid family and are abundantly present in cell membranes. These lipids were recently shown to interfere with the uptake of virus particles of SARS-CoV-2 into epithelial cell lines and primary human nasal cells in culture. The mechanisms of action were partly different, as sphingosine blocked, whilst ceramide facilitated viral entry. Acid sphingomyelinase (ASM) is vital for the generation of ceramide and functional inhibition of ASM by drugs like amitriptyline reduced SARS-CoV-2 entry into the epithelial cells. Recent data indicates that serum level of sphingosine-1-phosphate (S1P) is a prognostic factor for COVID-2 severity. Further, stimulation of sphingosine-1-phosphate receptor 1 (S1PR1) might also constrain the hyper-inflammatory conditions linked to SARS-CoV-2. Here, we review recent exciting findings regarding sphingolipids in the uptake of SARS-CoV-2 and in the course of COVID-19 disease. More studies are required on the mechanisms of action and the potential use of antidepressant drugs and sphingolipid modifiers in SARS-CoV-2 infections and in the treatment of the more serious and fatal consequences of the disease.
Insights
Sphingolipids impact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells; sphingosine blocks, ceramide aids uptake. Modulating these lipids, like with amitriptyline, may offer new COVID-19 treatments.
Area of Science:
- Molecular biology
- Virology
- Cell biology
- Biochemistry
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic, necessitating research into virus-host interactions.
- SARS-CoV-2 entry involves spike protein binding to ACE2 and protease priming, leading to endocytosis.
- Sphingolipids, such as sphingosine and ceramide, are cell membrane components with recently identified roles in viral uptake.
Purpose of the Study:
- To review recent findings on the role of sphingolipids in SARS-CoV-2 uptake and COVID-19 pathogenesis.
- To explore the potential therapeutic implications of targeting sphingolipid metabolism and signaling pathways in COVID-19.
Main Methods:
- Review of existing literature on sphingolipid involvement in SARS-CoV-2 infection.
- Analysis of studies investigating the effects of sphingosine and ceramide on viral entry into cell lines and primary human cells.
- Examination of data on acid sphingomyelinase (ASM) inhibition and sphingosine-1-phosphate (S1P)/S1PR1 signaling in the context of COVID-19.
Main Results:
- Sphingosine inhibits SARS-CoV-2 entry, while ceramide facilitates it, with distinct mechanisms in different cell types.
- Inhibition of acid sphingomyelinase (ASM), crucial for ceramide production, reduces viral entry; drugs like amitriptyline show potential.
- Serum sphingosine-1-phosphate (S1P) levels correlate with COVID-19 severity, and S1PR1 stimulation may mitigate hyperinflammation.
Conclusions:
- Sphingolipids play a complex, dual role in SARS-CoV-2 cellular entry.
- Targeting sphingolipid metabolism and signaling pathways, potentially using existing drugs like amitriptyline, presents a promising avenue for COVID-19 treatment.
- Further research is essential to elucidate mechanisms and optimize therapeutic strategies involving sphingolipid modifiers.
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