Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Wolf, Jennifer J.; Studstill, Caleb J.; Hahm, Bumsuk

doi:10.3390/v11121097

Cited by 27 publications

(22 citation statements)

References 97 publications

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“…SphK activation or expression was reported to be altered during several viral infection models (33,35,36,64,65). For instance, influenza and measles viruses were reported to increase the level of SphK1, which enhanced the replication and production of viruses.…”

Section: The Expression Of Sphk2 In Cd4 + T Cells But Not In Cd8 + Tmentioning

confidence: 99%

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Studstill¹,

Pritzl²,

Seo³

et al. 2020

Journal of Clinical Investigation

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Section: The Expression Of Sphk2 In Cd4 + T Cells But Not In Cd8 + Tmentioning

confidence: 99%

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Studstill¹,

Pritzl²,

Seo³

et al. 2020

Journal of Clinical Investigation

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“…Viruses manipulate cellular signalling. Examples of viral exploitation of SphK/S1P are influenza [ 217 ], measles [ 213 ], hepatitis B [ 218 ], dengue virus [ 219 ], the respiratory syncytial virus (RSV), hepatitis B virus (HBV), and hepatitis C viruses (HCV) [ 220 ].…”

Section: Targeting Sphk/s1p/s1pr In Viral Infection and Alleviatiomentioning

confidence: 99%

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

McGowan

Haddadi

Nassif

et al. 2020

IJMS

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The world is currently experiencing the worst health pandemic since the Spanish flu in 1918—the COVID-19 pandemic—caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the world’s third wake-up call this century. In 2003 and 2012, the world experienced two major coronavirus outbreaks, SARS-CoV-1 and Middle East Respiratory syndrome coronavirus (MERS-CoV), causing major respiratory tract infections. At present, there is neither a vaccine nor a cure for COVID-19. The severe COVID-19 symptoms of hyperinflammation, catastrophic damage to the vascular endothelium, thrombotic complications, septic shock, brain damage, acute disseminated encephalomyelitis (ADEM), and acute neurological and psychiatric complications are unprecedented. Many COVID-19 deaths result from the aftermath of hyperinflammatory complications, also referred to as the “cytokine storm syndrome”, endotheliitus and blood clotting, all with the potential to cause multiorgan dysfunction. The sphingolipid rheostat plays integral roles in viral replication, activation/modulation of the immune response, and importantly in maintaining vasculature integrity, with sphingosine 1 phosphate (S1P) and its cognate receptors (SIPRs: G-protein-coupled receptors) being key factors in vascular protection against endotheliitus. Hence, modulation of sphingosine kinase (SphK), S1P, and the S1P receptor pathway may provide significant beneficial effects towards counteracting the life-threatening, acute, and chronic complications associated with SARS-CoV-2 infection. This review provides a comprehensive overview of SARS-CoV-2 infection and disease, prospective vaccines, and current treatments. We then discuss the evidence supporting the targeting of SphK/S1P and S1P receptors in the repertoire of COVID-19 therapies to control viral replication and alleviate the known and emerging acute and chronic symptoms of COVID-19. Three clinical trials using FDA-approved sphingolipid-based drugs being repurposed and evaluated to help in alleviating COVID-19 symptoms are discussed.

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“…The effects of RhoA are often opposite to that of another small GTPase, Rac1, with both being induced by sphingosine-1-phosphate (S1P) receptors, S1P2/3r and S1P1r, respectively. Recent data shows S1P to significantly modulate viral infections (108). As S1P r subtypes have significant differential impacts on lipid raft reorganization (109), it will be important to determine the interactions of ACE2 receptors and α7nAChRs with S1Pr subtypes and dupα7/CHRFAM7A regulation in pulmonary epithelial cells and immune cells in SARS-CoV-2 pathophysiology.…”

Section: Treating Sars-cov-2 Symptomatologymentioning

confidence: 99%

COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

Anderson¹,

Reíter²

2020

Melatonin Res.

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As data emerges on the pathophysiological underpinnings of severe acute respiratory syndrome coronavirus (SARS-CoV)-2, it is clear that there are considerable variations in its susceptibility and severity/fatality, which give indications as to its pathophysiology and treatment. SARS-CoV-2 modulatory factors include age, vitamin D levels, cigarette smoking, gender and ethnicity as well as premorbid medical conditions, including diabetes, cancer, obesity, cardiovascular disease, and immune-compromised conditions. A complex picture is emerging, with an array of systemic physiological processes interacting including circadian, immune, intestinal, CNS and coagulation factors. This article reviews data on SARS-CoV-2 pathoetiology and pathophysiology. It is proposed that a decrease in pineal and systemic melatonin is an important driver of SARS-CoV-2 susceptibility and severity, with the loss of pineal melatonin's induction of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) in pulmonary epithelial cells and immune cells being a powerful regulator of susceptibility and severity, respectively. Stress, including discrimination stress, and decreased vitamin D also regulate SARS-CoV-2, including via gut dysbiosis and permeability, with a resultant decrease in the short-chain fatty acid, butyrate, and increase in circulating lipopolysaccharide. Stress and cytokine induction of the kynurenine pathways, leads to aryl hydrocarbon receptor activation, which primes platelets for heightened activity, coagulation and thrombin production, thereby driving elevations in thrombin that underpin many SARS-CoV-2 fatalities. On the basis of these pathophysiological changes, prophylactic and symptomatic treatments are proposed, including the use of melatonin and α7nAChR agonism.

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Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Cited by 27 publications

References 97 publications

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19

COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

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