Abstract
BackgroundOxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.MethodsDetection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA®) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).ResultsForty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.ConclusionsIt was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.
Highlights
Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initia‐ tion and resolution of inflammation during microbial infections
The endocannabinoid group was found to be more useful for discrimination between infected versus controls, with a total of four significant metabolites according to the t test with Bonferroni correction (OEA, palmitoyl ethanolamide (PEA), DEA and eicosapentaenoyl ethanolamide (EPEA))
More oxylipins were significant according to t-test without multisampling correction though, including three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) that were at significantly higher levels in severe compared to uncomplicated malaria cases
Summary
Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initia‐ tion and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism. The most dangerous form of the disease, severe Plasmodium falciparum malaria, is a complex syndrome characterized by the sequestration of parasitized erythrocytes in the peripheral vasculature and a profound imbalance between pro-and anti-inflammatory responses. The infection rapidly elicits complex shifts in metabolic pathways in all organ systems of the body, which leads to tissue damage [3]. Metabolic complications of malaria are increasingly recognized as contributors to severe and fatal malaria [4]. Transcriptomics and proteomics have been used in many studies of malaria, results obtained from application of these methods do not directly reflect the changes in the metabolism of the patient
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