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

ABSTRACT: Global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing. Before an effective vaccine is available, the development of potential treatments for resultant coronavirus disease 2019 (COVID-19) is crucial. One of the disease hallmarks is hyper-inflammatory responses, which usually leads to a severe lung disease. Patients with COVID-19 also frequently suffer from neurological symptoms such as acute diffuse encephalomyelitis, brain injury and psychiatric complications. The metabolic pathway of sphingosine-1-phosphate (S1P) is a dynamic regulator of various cell types and disease processes, including the nervous system. It has been demonstrated that S1P and its metabolic enzymes, regulating neuroinflammation and neurogenesis, exhibit important functions during viral infection. S1P receptor 1 (S1PR1) analogues including AAL-R and RP-002 inhibit pathophysiological responses at the early stage of H1N1 virus infection and then play a protective role. Fingolimod (FTY720) is an S1P receptor modulator and is being tested for treating COVID-19. Our review provides an overview of SARS-CoV-2 infection and critical role of the SphK-S1P-SIPR pathway in invasion of SARS-CoV-2 infection, particularly in the central nervous system (CNS). This may help design therapeutic strategies based on the S1P-mediated signal transduction, and the adjuvant therapeutic effects of S1P analogues to limit or prevent the interaction between the host and SARS-CoV-2, block the spread of the SARS-CoV-2, and consequently treat related complications in the CNS.

SUBMITTER: Pan Y

PROVIDER: S-EPMC8014301 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Coronaviruses belong to a well-known family of enveloped RNA viruses and the causative agent of the common cold. Although the seasonal coronaviruses do not pose a threat to human life, three members of this family, i.e., SARS-CoV, MERS-CoV and recently, SARS-CoV2, may cause severe acute respiratory syndrome that may lead to death. Unfortunately, COVID-19 has already caused more than 4,4 million deaths worldwide. Although much is better understood about the immunopathogenesis of the lung disease, important information about systemic disease is still missing, mainly concerning neurological parameters. In this context, we sought to evaluate immunometabolic changes using in vitro and in vivo models of hamsters infected with SARS-CoV2. Here show that, besides infecting and replicating in glial cells, SARS-CoV2 induces important changes in protein expression and metabolic pathways, specially involved in carbon metabolism, glycolysis, and mitochondrial respiration. Interestingly, many of the differentially expressed proteins during SARS-CoV2 infection overlapped with proteins correlated with neurological diseases, such as Parkinsons's Disease, multiple sclerosis, amyotrophic lateral sclerosis and Huntington's disease. Metabolic analysis by high resolution real-time respirometry evidenced hyperactivation of glycolysis and mitochondrial respiration, which was confirmed by metabolomics. Brain infection with SARS-CoV2 was confirmed in vivo as hippocampus, cortex and olfactory bulb of infected hamsters were positive for viral genome both at 4 and 7 days post-infection. Unexpectedly, we observed that glutamine was significantly reduced in mixed glial cells infected with SARS-CoV2 and that the blockade of glutaminolysis significantly reduced viral replication and pro-inflammatory response. Altogether, our data confirms the infection of brain cells by SARS-CoV2 but, most importantly, there is an important change in overall protein expression profile, mostly of proteins related to metabolic pathways. This may suggest that some of the neurological impairments observed during COVID-19, as the brain fog and cognitive impairment, may rely on altered protein expression and unbalanced glutamine/glutamate levels, whose importance for adequate brain function is unquestionable.

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

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