Avaliação da via de esfingosina 1-fosfato (S1P) e lipídios correlacionados ao metabolismo de ceramidas em pacientes infectados por SARS- COV-2

Abstract

The SARS-CoV-2 infection, responsible for COVID-19, initiates diverse pathophysiological pathways, leading to changes and disruptions in the host's immune response. Severe cases often manifest intense pulmonary inflammation with systemic repercussions. The storm of mediators, including lipids and cytokines, in severe patients contributes to tissue damage. Sphingolipids (SL) play fundamental roles in various cellular and tissue processes, including inflammation regulation, metabolic disorders, and even carcinogenesis. Our research used high-resolution mass spectrometry and RNAseq analysis to examine SL metabolism in plasma samples from control individuals (n = 55), COVID-19 patients (n = 204), and convalescent individuals (n = 77), correlating these data with clinical and inflammatory parameters related to disease severity. Additionally, we investigated in vitro the role of Sphingosine-1-phosphate receptor 1 (S1PR1) in SARS-CoV-2 viral replication and inflammatory activity in THP-1 human cell cultures resembling macrophages. Our analyses revealed alterations in SL species in the plasma of study participants, with the most significant changes observed in severe disease patients. The sphingomyelin (SM) species d18:1/24:0 and d18:1/24:1 were identified as potential severity biomarkers. Additionally, we observed a decrease in the expression of enzymes involved in the S1P pathway and its receptor S1PR1 in blood cells from severe COVID-19 patients. We also noted that S1P synthesis is related to the body's efforts to transition to the recovery and resolution phase of COVID-19, although it does not seem to exert a defined anti-inflammatory role. Our in vitro experiments demonstrated that blocking the S1PR1 receptor was effective in reducing viral replication and modulating the exacerbated immune response. Thus, our findings highlight the interaction between S1P production and sphingomyelins (SM), identified as potential severity biomarkers, with the immune system in COVID-19.