1H NMR metabonomics indicates continued metabolic changes and sexual dimorphism post-parasite clearance in self-limiting murine malaria model - PubMed (original) (raw)
1H NMR metabonomics indicates continued metabolic changes and sexual dimorphism post-parasite clearance in self-limiting murine malaria model
Arjun Sengupta et al. PLoS One. 2013.
Abstract
Malaria, a mosquito-borne disease caused by Plasmodium spp. is considered to be a global threat, specifically for the developing countries. In human subjects considerable information exists regarding post-malarial physiology. However, most murine malarial models are lethal, and most studies deal with acute phases occurring as disease progresses. Much less is known regarding physiological status post-parasite clearance. We have assessed the physiological changes at the organ levels using (1)H NMR based metabonomics in a non lethal self-clearing murine malarial model of P. chabaudi parasites and Balb/C, far beyond the parasite clearance point. The results showed distinct metabolic states between uninfected and infected mice at the peak parasitemia, as well as three weeks post-parasite clearance. Our data also suggests that the response at the peak infection as well as recovery exhibited distinct sexual dimorphism. Specifically, we observed accumulation of acetylcholine in the brain metabolic profile of both the sexes. This might have important implication in understanding the pathophysiology of the post malarial neurological syndromes. In addition, the female liver showed high levels of glucose, dimethylglycine, methylacetoacetate and histidine after three weeks post-parasite clearance, while the males showed accumulation of branched chain amino acids, lysine, glutamine and bile acids.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
Figure 1. The parasitemia kinetics of P. chabaudi infected Balb/C mice.
The parasitemia was calculated from RBCs counted on Giemsa stained blood smear. 400–500 RBCs were counted in each case.
Figure 2. Representative 700 MHz 1H NMR spectra of hydrophilic fraction of methanol/water/chloroform extract.
(A) serum, (B) brain and (C) liver from healthy uninfected mouse. Only aliphatic region of the spectra is shown. 1- Isoleucine/Leucine, 2- valine, 3- 3-hydroxybutyrate, 4- lactate, 5- alanine, 6- lysine, 7- acetate, 8- glutamate/glutamine, 9- succinate, 10- glutamine, 11- glutamate, 12- aspartate+lysine, 13- N+(CH3)3 head groups from GPC, PC and choline, 14- carbohydrates, polyols and amino acid ά-1H, 15- N-methylnicotinamide, 16- anomeric 1H of ά-glucose, 17- glycogen, 18- γ-aminobutyric acid, 19- N-acetylaspartate, 20- glutamate+N-acetylneuraminate, 21- aspartate, 22- creatine, 23- taurine+myo-inositol, 24- myo-inositol, 25- scyllo-inositol, 26- taurine, 27- lipid (LDL/VLDL- CH3(CH2)n),28- fucose, 29- lipids (CH2-C = C), 30- lipids (CH2-C = O), 31- oxaloacetate/pyruvate, 32- = C-CH2-C = .
Figure 3. The PCA scores plots of 1H NMR spectra of Balb/C mice infected with P. chabaudi illustrating the segregation of uninfected control animals from animals at the peak infection stage.
The scores plots generated from PC1 and PC2 are illustrated here. The plots represent pair-wise models of different biological compartments. A–C females and D–F males. A and D - liver, B and E- serum, C and F–brain. In each plot, red symbols are uninfected control mice and black dots represent animals at peak infection stage. Among the red symbols, the squares represent the control mice sacrificed along with the peak infection animals and the circles represent the animals sacrificed with the three weeks post-parasite clearance stage animals.
Figure 4. The PCA scores plots of 1H NMR spectra of Balb/C mice infected with P. chabaudi showing the segregation of uninfected control from infected mice three weeks post-parasite clearance.
The recovered time point was taken as the three week post parasite clearance. The plots represent pair-wise models of different biological compartments. A–C represent females and D–F males. A and D- liver, B and E – serum, C and F –brain. In each plot, the red dots are uninfected control and the blue dots represent the animals at three weeks post-parasite clearance. Among the red symbols, the squares represent the control mice sacrificed along with the peak infection animals and the circles represent the animals sacrificed with the three weeks post-parasite clearance animals.
Figure 5. The probable metabolic network affected during the peak infection stage in the female liver.
Metabolites marked in black are elevated during the peak infection stage and those in blue are lowered at this stage. Metabolites in orange font did not show any significant variation and/or not detected in the 1H NMR spectra.
Figure 6. Schematic of acetylcholine biosynthesis in the central nervous system.
Acetylcholine was found to be elevated in the both three weeks post-recovery male and female Balb/C mice infected with Plasmodium chabaudi. In addition, the female mice showed elevation in the level of phosphorylcholine and decrease in methionine.
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