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

Abstract

In the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), a better understanding of the underlying mechanisms is essential to reduce morbidity and mortality and treat post-COVID-19 disease. Here, we analyzed alterations of sphingolipids and their metabolizing enzymes in 125 men and 74 women tested positive for SARS-CoV-2 and hospitalized with mild, moderate or severe symptoms or after convalescence. The activities of acid and neutral sphingomyelinases (ASM, NSM), which hydrolyze sphingomyelin to ceramide, were significantly increased in COVID-19 patients, while the activity of neutral ceramidase (NC), which hydrolyzes ceramide to sphingosine, was reduced. These alterations could each contribute to elevated ceramide levels in patients. Accordingly, liquid chromatography tandem-mass spectrometry (LC-MS/MS) yielded increased levels of ceramides 16:0 and 18:0 with highest levels in severely affected patients and similar effects for dihydroceramides 16:0 and 18:0, whereas levels of (dihydro-)ceramides 24:0 were reduced. Furthermore, sphingomyelin 20:0; 22:0 and 24:0 as substrates of ASM and NSM as well as their dihydrosphingomyelin counterparts were reduced in patients as well as sphingosine-1-phosphate further downstream of NC activity. Effects of NSM, NC, ceramides and sphingomyelins remained significant after Bonferroni correction. SARS-CoV-2 antibody levels in convalescent patients were associated with age but none of the sphingolipid parameters. Based on our data, COVID-19 is associated with a dysregulation of sphingolipid homeostasis in a severity-dependent manner, particularly focused around a reduction of sphingomyelins and an accumulation of ceramides by increased enzyme activities leading to ceramide elevation (ASM, NSM) combined with a decreased activity of enzymes (NC) reducing ceramide levels. The potential of a combined sphingolipid/enzyme pattern as a diagnostic and prognostic marker and therapeutic target deserves further exploration.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19

“…We found that the use of antidepressants with high FIASMA activity, comprising specific SSRI and non-SSRI molecules, was significantly less prevalent in adult inpatients who tested positive versus negative for the SARS-CoV-2 in a matched analytic sample, and significantly associated with reduced mortality. These findings are in line with prior preclinical [ 45 ] and observational [ 28 , 29 ] study results, suggesting the utility of medications with FIASMA activity against COVID-19 disease progression, as well as studies showing that plasma levels of ceramides and enzyme activities of sphingomyelinase and ceramidase strongly correlate with disease clinical severity and inflammation markers in patients with COVID-19 [ 60 , 61 , 62 , 63 , 64 ]. Inhibition of the ASM catalyzing the formation of ceramides [ 50 , 65 ] by FIASMA antidepressants may result in two effects: antiviral—through the reduced formation of ceramide-enriched membrane domains that facilitate SARS-CoV-2 entry in cells, and anti-inflammatory—through the inhibition of ASM in endothelial cells and the immune system [ 7 , 12 ].…”

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2

“…b Models were adjusted for sex, age, race and ethnicity, obesity, number of diagnoses, history of mood or anxiety disorder, history of other psychiatric disorders, number of home medications, concurrent exposure to benzodiazepine or Z drug, concurrent exposure to antipsychotic drugs, and concurrent exposure to non-antidepressant drugs with FIASMA or S1R activity (listed in Table S1). markers [42][43][44][45], lending further support for FIASMA as an explanatory mechanism behind the associations reported in observational studies.…”

The effect of antidepressants on the severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis

“…In an investigation held by Enrica Torretta et al, the sphingolipid profile of twenty-four healthy and fifty-nine COVID-19 patients was analyzed and the correlation between the level of ceramide with the disease’s severity demonstrated [ 52 ]. This increase in ceramide level can be attributable to increased activity of acid and neutral sphingomyelinases(ASM, NSM) or a reduction in neutral ceramidase (NC) activity [ 53 ].…”