The acid sphingomyelinase/ceramide system in COVID-19

Abstract

Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of “old” drugs against COVID-19.

Antidepressant drug treatment protecting from COVID-19: one more piece in the repurposing puzzle

“…First, antidepressants have been shown to interact with the sphingomyelinase/ceramide system, which is likely required to facilitate angiotensin-converting enzyme 2 (ACE2) binding of the SARS-CoV-2 and thereby impair viral host cell entry. [10][11][12] In addition to antidepressant drugs, several medications share the property of functional inhibition of the acid sphingomyelinase. Recent observational data show a reduced likelihood of intubation or death in (n = 2846) COVID-19-infected patients who are treated with any of the functional sphingomyelinase/ceramide system inhibitory drugs.…”

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

“…To contain the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a better understanding of the underlying mechanisms and the high interindividual differences in susceptibility is essential. A number of recent studies point to changes in the sphingolipid metabolism (Kornhuber et al 2021). Sphingolipids such as sphingomyelin (SM) and ceramide (Cer) not only serve as physical membrane components and as ligands on their own, but they also influence the local composition and fluidity of the plasma membrane and thereby the localization and activity of proteins involved in receptor-mediated signaling (Hannun and Obeid 2018).…”

“…These drugs were therefore named functional inhibitors of ASM (FIASMA, (Kornhuber et al 2010)) and include commonly used antidepressants like fluoxetine, amitriptyline and fluvoxamine. Interestingly, an antiviral effect of FIASMAs against SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV and also especially SARS-CoV-2 has been demonstrated by various approaches in silico, in vitro and in vivo as summarized in recent reviews (Kornhuber et al 2021;Le Corre and Loas 2021) (Loas and Le Corre 2021). SARS-CoV-2 is thought to activate the ASM/Cer system, resulting in the formation of Cer-enriched membrane domains (Carpinteiro et al 2020) (Schneider-Schaulies et al 2021) and clustering of angiotensin-converting enzyme 2 (ACE2), the cellular receptor of SARS-CoV-2.…”

Ongoing Use of SSRIs Does Not Alter Outcome in Hospitalized COVID-19 Patients: A Retrospective Analysis

“…Interestingly, it has been found that the COVID-19 virus activates the ceramide system that then facilitates viral entry into cells [ 27 ]. The sphingomyelin/ceramide system can be altered by SSRIs so that ceramide levels are reduced and this may prevent COVID-19 replication [ 28 , 29 , 30 ].…”