Alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression

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.

Central carbon metabolism of Plasmodium parasites

“…Such techniques have been used to probe metabolic perturbations induced by malarial infection in in vitroP. falciparum cultures [80] and in vivo rodent malaria models [101, 102]. More directly, the ability of analytic technologies such as mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy to trace the flow of heavy isotope-labeled nutrients through pathways is proving to be exceptionally valuable in this regard.…”

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…Nuclear magnetic resonance or gas/liquid chromatography coupled with mass spectrometry (GC/LC-MS) have been applied to understand the metabolic changes in models of host- Plasmodium interactions in vitro (Lakshmanan et al, 2012; MacRae et al, 2013; O’Hara et al, 2014; Olszewski et al, 2009; Park et al, 2015; Sana et al, 2013) and in vivo (Basant et al, 2010; Ghosh et al, 2012, 2013; Olszewski et al, 2009; Sengupta et al, 2013; Tritten et al, 2013). However, studies of human malaria are limited to evaluation of plasma from patients infected with P. falciparum (Lakshmanan et al, 2012; Surowiec et al, 2015; Sengupta et al, 2016) or urine from patients infected with P. vivax (Sengupta et al, 2011).…”

NMR-Based Metabolomics and Its Application in Drug Metabolism and Cancer Research

“…Furthermore, stable isotope approaches make it possible to understand and measure flux through specific pathways, which provides the metabolic rate or metabolic path as opposed to the starting and final concentration of metabolites [14,15]. With this information, NMR-based metabolomics has been successfully used in toxicology [4,16,17], pathophysiology [18,19], understanding gene function [20], and for rapid diagnosis, therapeutics, and prognosis of metabolic disease using cell, animal models, and human samples [21,22] (Fig. 1a).…”