Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature

Abstract

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient’s outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution.

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

“…Our data fit well with previous studies showing in COVID-19 patients an up-regulation of the Cersignaling pathway (Alexander et al 2021) and increased levels of Cer (Marin-Corral et al 2021) (Abusukhun et al 2021;Khodadoust 2021;Torretta et al 2021) with Cer 24:0 as the solely decreased species (Torretta et al 2021) as in our study. They are also in accordance with literature on increased dihydroceramide and decreased sphingomyelin in a cohort of 83 subjects (Torretta et al 2021). We additionally show a decrease in dihydrosphingomyelin counterparts of sphingomyelin species.…”

“…Despite the central role of enzymes involved in the regulation of Cer levels and the availability of inhibitors such as FIASMAs and thus their potential as prospective therapeutic targets, reports on these enzymes and particularly their activities are largely lacking so far apart from two studies at protein level and a very recent report on ASM activity: Our data on increased ASM activity in a larger cohort confirms the previously reported higher levels of ASM protein determined by ELISA in severely affected subjects from a total of 59 patients (Torretta et al 2021) and the most recently observed increased serum ASM activities in 23 intensive care patients with COVID-19 assayed by a different method using mass spectrometry (Abusukhun et al 2021). Whereas -to our knowledge -there are no data on NSM and NC activities in COVID-19 patients yet, our findings are also in perfect agreement with their contribution to increased ceramide and reduced sphingomyelin levels.…”

“…In patients with SARS-CoV-2 (COVID-19 patients), the Cer-signaling pathway was noted to be upregulated (Alexander et al 2021). Cer concentrations were found to be increased in the plasma of COVID-19 patients per se (Marin-Corral et al 2021) (Lee et al 2021a) and an additional increase was seen in patients with severe respiratory symptoms (Khodadoust 2021;Torretta et al 2021). Furthermore, reduced serum sphingosine levels were highly associated with symptomatic COVID-19 compared to asymptomatic SARS-CoV-2 antibody-positive donors (Janneh et al 2021).…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Additionally, some of the purple module hub-high traffic genes, such as MAPK1 ( 189 , 374 ), CUL2 ( 210 ), CMTM6 ( 162 ), TXNRD1 ( 375 ), RAB1A ( 376 ), DICER1 ( 377 ), RAB5A ( 209 ), HSP90B1 ( 343 ), MAGT1 ( 378 ), ADAM10 ( 379 , 380 ), SNX2 ( 89 ), OLA1 ( 381 ), SPTLC1 ( 382 ), SH3GLB1 ( 383 ), TIMM10B ( 384 ), and CREB1 ( 385 ) hub-high traffic TF, which are central for information exchange in this module, are potential targets for development of COVID-19 therapeutic strategies. Among these, the mitogen-activated protein kinase 1 ( MAPK1 ) hub-high traffic gene is a potential core target for many anti-COVID-19 therapeutic strategies ( 189 , 374 , 386 – 390 ).…”

Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study

“…In an observational multicenter retrospective study, use of a FIASMA medication upon hospital admission was associated with a substantially reduced risk of intubation or death [23]. Finally, plasma levels of certain sphingolipids, particularly sphingomyelins and ceramides, were found to correlate with disease clinical severity [29][30][31], inflammation markers [29,30] and viral load [30,31] in patients with COVID-19. Altogether, these data support the central role of ASM/ceramide system in SARS-CoV-2 infection that could be targeted by hydroxyzine, even if the magnitude of the in vitro FIASMA effect of this treatment (i.e., in vitro residual ASM activity of 43%) is slightly lower than that of fluoxetine (13%) and fluvoxamine (37.4%) [18].…”