SARS-CoV-2 Infection: A Role for S1P/S1P Receptor Signaling in the Nervous System?

Abstract

The recent coronavirus disease (COVID-19) is still spreading worldwide. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, binds to its receptor angiotensin-converting enzyme 2 (ACE2), and replicates within the cells of the nasal cavity, then spreads along the airway tracts, causing mild clinical manifestations, and, in a majority of patients, a persisting loss of smell. In some individuals, SARS-CoV-2 reaches and infects several organs, including the lung, leading to severe pulmonary disease. SARS-CoV-2 induces neurological symptoms, likely contributing to morbidity and mortality through unknown mechanisms. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with pleiotropic properties and functions in many tissues, including the nervous system. S1P regulates neurogenesis and inflammation and it is implicated in multiple sclerosis (MS). Notably, Fingolimod (FTY720), a modulator of S1P receptors, has been approved for the treatment of MS and is being tested for COVID-19. Here, we discuss the putative role of S1P on viral infection and in the modulation of inflammation and survival in the stem cell niche of the olfactory epithelium. This could help to design therapeutic strategies based on S1P-mediated signaling to limit or overcome the host–virus interaction, virus propagation and the pathogenesis and complications involving the nervous system.

Functions of Sphingolipids in Pathogenesis During Host–Pathogen Interactions

“…Exogenously applied sphingosine prevents the interaction of the receptor-binding domain of the viral S protein with ACE2, indicating that sphingosine might be used as a novel drug to prevent SARS-CoV-2 infection ( Edwards et al, 2020 ). SARS-CoV-2 infection could impair the activities of enzymes involved in S1P synthesis and the signaling triggered by S1P, thereby affecting the ability of the virus to promote multiple clinical symptoms and the individual response to the virus ( Meacci et al, 2020 ). GCS inhibitors disrupt early stages of SARS-CoV-2 replication and significantly reduced the levels of N protein in infected cells, suggesting that the synthesis of GlcCer is required to support the viral lifecycle ( Vitner et al, 2021 ).…”

Biology of COVID-19 and related viruses: Epidemiology, signs, symptoms, diagnosis, and treatment

“…Certain regions of the S protein have also enabled the differentiation of SARS-CoV-2 from SARS-CoV and improved specificity of serologic testing [ 30 ]. Through the function of the S protein, SARS-CoV-2 is believed to replicate in the olfactory epithelium of the nasal cavity and spread along the tracts of the airway [ 31 ]. It is this initial locus of replication that is thought to explain the clinical manifestation of loss of smell experienced by some individuals [ 31 ].…”

“…Through the function of the S protein, SARS-CoV-2 is believed to replicate in the olfactory epithelium of the nasal cavity and spread along the tracts of the airway [ 31 ]. It is this initial locus of replication that is thought to explain the clinical manifestation of loss of smell experienced by some individuals [ 31 ]. In more severe cases, SARS-CoV-2 travels along the airway to the lungs to cause severe pulmonary disease with potential systemic sequelae such as neurologic symptoms and multi-tissue dysfunction [ 31 , 32 ].…”

“…It is this initial locus of replication that is thought to explain the clinical manifestation of loss of smell experienced by some individuals [ 31 ]. In more severe cases, SARS-CoV-2 travels along the airway to the lungs to cause severe pulmonary disease with potential systemic sequelae such as neurologic symptoms and multi-tissue dysfunction [ 31 , 32 ]. Wide tissue dissemination of the virus is believed to result from the presence of targets, in the form of the ACE2 receptor, on various tissue types, including the cardiovascular system, gastrointestinal tract, and central nervous system [ 27 ].…”

The Anti-Infectious Role of Sphingosine in Microbial Diseases

“…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 ].…”