Abstract
BackgroundMetabolic changes in the host in response to Plasmodium infection play a crucial role in the pathogenesis of malaria. Alterations in metabolism of male and female mice infected with Plasmodium berghei ANKA are reported here.Methods1H NMR spectra of urine, sera and brain extracts of these mice were analysed over disease progression using Principle Component Analysis and Orthogonal Partial Least Square Discriminant Analysis.ResultsAnalyses of overall changes in urinary profiles during disease progression demonstrate that females show a significant early post-infection shift in metabolism as compared to males. In contrast, serum profiles of female mice remain unaltered in the early infection stages; whereas that of the male mice changed. Brain metabolite profiles do not show global changes in the early stages of infection in either sex. By the late stages urine, serum and brain profiles of both sexes are severely affected. Analyses of individual metabolites show significant increase in lactate, alanine and lysine, kynurenic acid and quinolinic acid in sera of both males and females at this stage. Early changes in female urine are marked by an increase of ureidopropionate, lowering of carnitine and transient enhancement of asparagine and dimethylglycine. Several metabolites when analysed individually in sera and brain reveal significant changes in their levels in the early phase of infection mainly in female mice. Asparagine and dimethylglycine levels decrease and quinolinic acid increases early in sera of infected females. In brain extracts of females, an early rise in levels is also observed for lactate, alanine and glycerol, kynurenic acid, ureidopropionate and 2-hydroxy-2-methylbutyrate.ConclusionsThese results suggest that P. berghei infection leads to impairment of glycolysis, lipid metabolism, metabolism of tryptophan and degradation of uracil. Characterization of early changes along these pathways may be crucial for prognosis and better disease management. Additionally, the distinct sexual dimorphism exhibited in these responses has a bearing on the understanding of the pathophysiology of malaria.
Highlights
Metabolic changes in the host in response to Plasmodium infection play a crucial role in the pathogenesis of malaria
For an overview of our dataset, to determine its quality and to identify samples that are serious outliers, first Principle Component Analysis was performed. This established in an unsupervised manner, whether Plasmodium infection changed the metabolism in the host
All subsequent analyses were carried out by a priori assignment of samples into classes of either uninfected and infected or male and female. This was done by Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA)
Summary
Metabolic changes in the host in response to Plasmodium infection play a crucial role in the pathogenesis of malaria. Plasmodium is the causative organism of malaria which affects 200-300 million people and causes nearly one million deaths annually [1]. This poses a serious, global health problem. During the acute stages of the disease more than one tissue type of the host is known to be affected [2,3]. Metabolites in body fluids and tissues that correlate with progression of the disease may serve as useful indicators of these changes. These metabolites may underscore the metabolic pathways that are perturbed in the host in response to infection
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