Acetylcholine, Fatty Acids, and Lipid Mediators Are Linked to COVID-19 Severity

Abstract

on behalf of the ImmunoCOVID Brazilian Research Consortium 3Lipid and cholinergic mediators are inflammatory regulators, but their role in the immunopathology of COVID-19 is still unclear. Here, we used human blood and tracheal aspirate (TA) to investigate whether acetylcholine (Ach), fatty acids (FAs), and their derived lipid mediators (LMs) are associated with COVID-19 severity. First, we analyzed the perturbation profile induced by SARS-CoV-2 infection in the transcriptional profile of genes related to the ACh and FA/LM pathways. Blood and TA were used for metabolomic and lipidomic analyses and for quantification of leukocytes, cytokines, and ACh. Differential expression and coexpression gene network data revealed a unique transcriptional profile associated with ACh and FA/LM production, release, and cellular signaling. Transcriptomic data were corroborated by laboratory findings: SARS-CoV-2 infection increased plasma and TA levels of arachidonic acid, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, 11-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid, and ACh. TA samples also exhibited high levels of PGE 2 , thromboxane B 2 , 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid, and 6-trans-leukotriene B 4 . Bioinformatics and experimental approaches demonstrated robust correlation between transcriptional profile in Ach and FA/LM pathways and parameters of severe COVID-19. As expected, the increased neutrophil-to-lymphocyte ratio, neutrophil counts, and cytokine levels (IL-6, IL-10, IL-1b, and IL-8) correlated with worse clinical scores. Glucocorticoids protected severe and critical patients and correlated with reduced Ach levels in plasma and TA samples. We demonstrated that pulmonary and systemic hyperinflammation in severe COVID-19 are associated with high levels of Ach and FA/LM. Glucocorticoids favored the survival of patients with severe/critical disease, and this effect was associated with a reduction in ACh levels.

The Severity of COVID-19 Affects the Plasma Soluble Levels of the Immune Checkpoint HLA-G Molecule

“…To understand the reciprocal influence of cytokines and sHLA-G levels, we performed several correlational analyses among these soluble molecules. As observed in this study and others, IL-6, IL-8 and IL-10 have systematically been reported as increased in COVID-19, particularly in the acute phase of the disease [ 49 ]. Considering that sHLA-G levels were increased in COVID-19 patients, irrespective of disease severity, the increased sHLA-G levels occurred together with the currently reported inflammatory IL-6, IL-8, and IL-10 cytokines, and positive correlations were observed between sHLA-G and these cytokines; only IL-10 has a well-recognized role on the induction of the HLA-G gene expression [ 50 ].…”

High mobility group box 1, ATP, lipid mediators, and tissue factor are elevated in COVID‐19 patients: HMGB1 as a biomarker of worst prognosis

“…In the same line, eicosanoids such as cys‐LTs, PGE 2 , and LTB 4 are also released by ATP and HMGB1 stimuli 18,41–43 . In agreement, some data in the literature demonstrated that lipid mediators were increased in patients with severe COVID‐19 and may be associated with poor outcomes 31,44 . Meanwhile, the role of eicosanoids in COVID‐19 remains to be characterized.…”

Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19

“…Not only metabolites but also lipids such as carnitines and phosphatidylcholine ( Caterino et al, 2021b ; D’alessandro et al, 2021 ; Wu et al, 2022 ) and an NMR-determined pro-atherogenic lipoprotein profile have been associated to COVID-19 severity ( Schmelter et al, 2021 ; Rendeiro et al, 2022 ). In addition, the metabolic changes associated with severity are also correlated with immune response markers: between plasma oxylipins ( Karu et al, 2022 ) or acetylcholine ( Pérez et al, 2022 ) with chemokines/neutrophiles or between lysophosphatidyl choline (LPC) with IL-6 ( Sindelar et al, 2021 ).…”