Role of the SphK‐S1P‐S1PRs pathway in invasion of the nervous system by SARS‐CoV‐2 infection

Pan, Yuehai; Gao, Fei; Zhao, Shuai; Han, Jinming; Chen, Fan

doi:10.1111/1440-1681.13483

Cited by 13 publications

(12 citation statements)

References 165 publications

(233 reference statements)

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“…Increasing attention is being paid to the involvement of sphingolipids in viral infection and replication in general (reviewed in 33,42,43 ) and SARS viruses in particular. [44][45][46][47][48] Entry of SARS viruses into target cells is primarily mediated by binding to angiotensin-converting enzyme 2 (ACE2), followed by proteolytic cleavage by TMPRSS2 and internalization via endocytosis mediated by lipid rafts, which are cholesterol-and sphingolipid-rich membrane domains. 49 McGowan et al 44 40 Because of the positive efficacy of opaganib against Covid-19, definition of the biochemical mechanism(s) for this activity requires further investigation.…”

Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Smith¹,

Maines²,

Keller³

et al. 2022

DDDT

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The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

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Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Smith¹,

Maines²,

Keller³

et al. 2022

DDDT

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“…The causes of stroke are diverse and the pathogenesis varies, ultimately leading to brain parenchymal necrosis, characterized by endothelial dysfunction and neuroinflammation, with the main pathological processes in the early stages of damage being resident inflammatory cells, rapid activation of inflammatory cytokines, and intercellular nuclear factors' translocation ( 85 , 86 ).…”

Section: Lymphatic Circulation Of the Cns And Its Related Diseasesmentioning

confidence: 99%

Research Progress on Intracranial Lymphatic Circulation and Its Involvement in Disorders

2022

Self Cite

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The lymphatic system is an important part of the circulatory system, as an auxiliary system of the vein, which has the functions of immune defense, maintaining the stability of the internal environment, and regulating the pressure of the tissue. It has long been thought that there are no typical lymphatic vessels consisting of endothelial cells in the central nervous system (CNS). In recent years, studies have confirmed the presence of lymphatic vessels lined with endothelial cells in the meninges. The periventricular meninges of the CNS host different populations of immune cells that affect the immune response associated with the CNS, and the continuous drainage of interstitial and cerebrospinal fluid produced in the CNS also proceeds mainly by the lymphatic system. This fluid process mobilizes to a large extent the transfer of antigens produced by the CNS to the meningeal immune cells and subsequently to the peripheral immune system through the lymphatic network, with clinically important implications for infectious diseases, autoimmunity, and tumor immunology. In our review, we discussed recent research advances in intracranial lymphatic circulation and the pathogenesis of its associated diseases, especially the discovery of meningeal lymphatic vessels, which has led to new therapeutic targets for the treatment of diseases associated with the intracranial lymphatic system.

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“…Recent studies indicate that fingolimod (FTY720), a sphingosine analog, already approved for the treatment of multiple sclerosis (MS), may help prevent the more serious neurological side-effects of SARS-CoV-2 infection [ 89 , 90 , 91 ]. FTY720 requires sphingosine kinase (Sphk) for activation and phosphorylation and blocks the inflammatory reaction mediated by sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor (S1PR)1 [ 92 , 93 ].…”

Section: The Role Of Sphingosine In Infectious Diseasesmentioning

confidence: 99%

“…Therefor defense strategy against SARS-CoV-2 infection [37]. To date, it i sphingosine has a direct antiviral effect on SARS-CoV-2 or HSV-Recent studies indicate that fingolimod (FTY720), a sphi approved for the treatment of multiple sclerosis (MS), may help neurological side-effects of SARS-CoV-2 infection [89][90][91]. FTY7 kinase (Sphk) for activation and phosphorylation and blocks th mediated by sphingosine-1-phosphate (S1P)/sphingosine-1-pho [92,93].…”

Section: Sphingosine and Virusesmentioning

confidence: 99%

“…Fungal infections are increasingly coming into focus due immune-deficient patients, such as those who have immunosuppressant medications. Cryptococcosis, candidiasis severe invasive mycoses with high mortality in immunocompro Recent studies indicate that fingolimod (FTY720), a sphingosine analog, already approved for the treatment of multiple sclerosis (MS), may help prevent the more serious neurological side-effects of SARS-CoV-2 infection [89][90][91]. FTY720 requires sphingosine kinase (Sphk) for activation and phosphorylation and blocks the inflammatory reaction mediated by sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor (S1PR)1 [92,93].…”

Section: Sphingosine and Fungimentioning

confidence: 99%

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The Anti-Infectious Role of Sphingosine in Microbial Diseases

Liu

Gulbins

et al. 2021

Cells

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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.

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Role of the SphK‐S1P‐S1PRs pathway in invasion of the nervous system by SARS‐CoV‐2 infection

Cited by 13 publications

References 165 publications

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Research Progress on Intracranial Lymphatic Circulation and Its Involvement in Disorders

The Anti-Infectious Role of Sphingosine in Microbial Diseases

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