Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Imunopathological Factor and a Severity Prognostic Biomarker in COVID-19

Version 1 : Received: 9 June 2023 / Approved: 12 June 2023 / Online: 12 June 2023 (04:10:26 CEST)

A peer-reviewed article of this Preprint also exists.

Toro, D.M.; da Silva-Neto, P.V.; de Carvalho, J.C.S.; Fuzo, C.A.; Pérez, M.M.; Pimentel, V.E.; Fraga-Silva, T.F.C.; Oliveira, C.N.S.; Caruso, G.R.; Vilela, A.F.L.; Nobre-Azevedo, P.; Defelippo-Felippe, T.V.; Argolo, J.G.M.; Degiovani, A.M.; Ostini, F.M.; Feitosa, M.R.; Parra, R.S.; Vilar, F.C.; Gaspar, G.G.; Rocha, J.J.R.; Feres, O.; Costa, G.P.; Maruyama, S.R.C.; Russo, E.M.S.; Fernandes, A.P.M.; Santos, I.K.F.M.; Malheiro, A.; Sadikot, R.T.; Bonato, V.L.D.; Cardoso, C.R.B.; Dias-Baruffi, M.; Trapé, Á.A.; Faccioli, L.H.; Sorgi, C.A.; ImmunoCovid Consortium Group. Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Immunopathological Factor and a Severity Prognostic Biomarker in COVID-19. Cells 2023, 12, 1938. Toro, D.M.; da Silva-Neto, P.V.; de Carvalho, J.C.S.; Fuzo, C.A.; Pérez, M.M.; Pimentel, V.E.; Fraga-Silva, T.F.C.; Oliveira, C.N.S.; Caruso, G.R.; Vilela, A.F.L.; Nobre-Azevedo, P.; Defelippo-Felippe, T.V.; Argolo, J.G.M.; Degiovani, A.M.; Ostini, F.M.; Feitosa, M.R.; Parra, R.S.; Vilar, F.C.; Gaspar, G.G.; Rocha, J.J.R.; Feres, O.; Costa, G.P.; Maruyama, S.R.C.; Russo, E.M.S.; Fernandes, A.P.M.; Santos, I.K.F.M.; Malheiro, A.; Sadikot, R.T.; Bonato, V.L.D.; Cardoso, C.R.B.; Dias-Baruffi, M.; Trapé, Á.A.; Faccioli, L.H.; Sorgi, C.A.; ImmunoCovid Consortium Group. Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Immunopathological Factor and a Severity Prognostic Biomarker in COVID-19. Cells 2023, 12, 1938.

Abstract

SARS-CoV-2 infection triggers distinct patterns of disease development, characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SL) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n=55), COVID-19 patients (n=204), and convalescent individuals (n=77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, the predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) d18:1/24:1 and d18:1/24:0 was associated with increased risk. Moreover, we observed enhanced expression of key enzymes involved in SL pathway, in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

Keywords

Sphingolipids; Sphingomyelin; Biomarker; COVID-19; Inflammation

Subject

Biology and Life Sciences, Immunology and Microbiology

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