1H NMR-based metabonomics was used to investigate the multimodal response of mice to malarial parasite infection by P. berghei ANKA. Liver metabolism was followed by NMR spectroscopy through the course of the disease in both male and female mice. Our results showed alterations in the level of several metabolites as a result of the infection. Metabolites like kynurenic acid, alanine, carnitine, and β-alanine showed significant alteration in the liver, suggesting altered kynurenic acid, glucose, fatty acid and amino acid pathways. Distinct sexual dimorphism was also observed in the global analysis of the liver metabolic profiles. Multiway principal component analysis (MPCA) was carried out on the liver, brain, and serum metabolic profile in order to explore the correlation of liver and brain metabolic profile to the metabolite profile of serum. Changes in such correlation profile also indicated distinct sexual dimorphism at the early stage of the disease. Indications are that the females are able to regulate their metabolism in the liver in such a way to maintain homeostasis in the blood. In males, however, choline in liver showed anticorrelation to choline content of serum indicating a higher phospholipid degradation process. The brain-serum correlation profile showed an altered energy metabolism in both the sexes. The differential organellar responses during disease progression have implications in malaria management. 1. Introduction Plasmodium is the organism responsible for malaria. It affects 200–300 million people and leads to a million deaths annually [1], thereby posing a global threat. The clinical symptoms of the infection are manifested during the blood stage of the parasite life cycle in the human host [2]. In acute stages of the disease, more than one tissue types are known to be affected [2, 3]. It was shown that during this stage of the disease, the parasitized RBCs show sequestration thereby affecting the microvasculature of heart, kidney, liver, intestines, adipose tissues, and eyes [4–6]. This may result in localized metabolic stress. As the disease progresses towards severity, several complications arise, possibly due to the inflammatory immune response of the host which result in complications such as liver damage, renal failure, cerebral malaria, hypoglycemia and acidosis, some of which may lead to death [7–9]. Although, the transition into these conditions is poorly understood, all of them are associated with different metabolic complications. Thus, one approach towards understanding the disease progression is to understand the
References
[1]
T. E. Wim Van Lerberghe, R. Kumanan, and M. Abdelhay, World Malaria Report, World Health Organization, 2008.
[2]
L. H. Miller, D. I. Baruch, K. Marsh, and O. K. Doumbo, “The pathogenic basis of malaria,” Nature, vol. 415, no. 6872, pp. 673–679, 2002.
[3]
M. F. Penet, F. Kober, S. Confort-Gouny et al., “Magnetic resonance spectroscopy reveals an impaired brain metabolic profile in mice resistant to cerebral malaria infected with Plasmodium berghei ANKA,” Journal of Biological Chemistry, vol. 282, no. 19, pp. 14505–14514, 2007.
[4]
A. M. Dondorp, P. A. Kager, J. Vreeken, and N. J. White, “Abnormal blood flow and red blood cell deformability in severe malaria,” Parasitology Today, vol. 16, no. 6, pp. 228–232, 2000.
[5]
G. G. MacPherson, M. J. Warrell, N. J. White, S. Looareesuwan, and D. A. Warrell, “Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration,” American Journal of Pathology, vol. 119, no. 3, pp. 385–401, 1985.
[6]
A. M. Dondorp, E. Pongponratn, and N. J. White, “Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology,” Acta Tropica, vol. 89, no. 3, pp. 309–317, 2004.
[7]
K. Haldar, S. C. Murphy, D. A. Milner, and T. E. Taylor, “Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease,” Annual Review of Pathology, vol. 2, pp. 217–249, 2007.
[8]
T. Planche and S. Krishna, “Severe malaria: metabolic complications,” Current Molecular Medicine, vol. 6, no. 2, pp. 141–153, 2006.
[9]
A. Trampuz, M. Jereb, I. Muzlovic, and R. M. Prabhu, “Clinical review: severe malaria,” Critical Care, vol. 7, no. 4, pp. 315–323, 2003.
[10]
J. K. Nicholson, J. Connelly, J. C. Lindon, and E. Holmes, “Metabonomics: a platform for studying drug toxicity and gene function,” Nature Reviews Drug Discovery, vol. 1, no. 2, pp. 153–161, 2002.
[11]
I. Barba, G. de León, E. Martín et al., “Nuclear magnetic resonance-based metabolomics predicts exercise-induced ischemia in patients with suspected coronary artery disease,” Magnetic Resonance in Medicine, vol. 60, no. 1, pp. 27–32, 2008.
[12]
T. L. Whitehead and T. Kieber-Emmons, “Applying in vitro NMR spectroscopy and 1H NMR metabonomics to breast cancer characterization and detection,” Progress in Nuclear Magnetic Resonance Spectroscopy, vol. 47, no. 3-4, pp. 165–174, 2005.
[13]
V. P. M？kinen, P. Soininen, C. Forsblom et al., “1H NMR metabonomics approach to the disease continuum of diabetic complications and premature death,” Molecular Systems Biology, vol. 4, article 167, 2008.
[14]
E. Holmes, R. L. Loo, J. Stamler et al., “Human metabolic phenotype diversity and its association with diet and blood pressure,” Nature, vol. 453, no. 7193, pp. 396–400, 2008.
[15]
Y. Wang, E. Holmes, J. K. Nicholson et al., “Metabonomic investigation in mice infected with Schistosoma mansoni: an approach for biomarker Identification,” Prot Nat Acad Sci USA, vol. 101, no. 34, pp. 12676–12681, 2004.
[16]
Y. Wang, J. Utzinger, J. Saric et al., “Global metabolic response of mice to trypanosoma brucei brucei infection,” Prot Nat Acad Sci USA, vol. 105, no. 16, pp. 6127–6132, 2008.
[17]
A. Basant, M. Rege, S. Sharma, and H. M. Sonawat, “Alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression,” Malaria Journal, p. 110, 2010.
[18]
I. Montoliu, F. P. J. Martin, S. Collino, S. Rezzi, and S. Kochhar, “Multivariate modeling strategy for intercompartmental analysis of tissue and plasma 1H NMR spectrotypes,” Journal of Proteome Research, vol. 8, no. 5, pp. 2397–2406, 2009.
[19]
E. F. Roth, M. C. Calvin, I. Max-Audit, J. Rosa, and R. Rosa, “The enzymes of the glycolytic pathway in erythrocytes infected with Plasmodium falciparum malaria parasites,” Blood, vol. 72, no. 6, pp. 1922–1925, 1988.
[20]
W. C. Kruckeberg, B. J. Sander, and D. C. Sullivan, “Plasmodium berghei: glycolytic enzymes of the infected mouse erythrocyte,” Experimental Parasitology, vol. 51, no. 3, pp. 438–443, 1981.
[21]
M. Mehta, H. M. Sonawat, and S. Sharma, “Malaria parasite-infected erythrocytes inhibit glucose utilization in uninfected red cells,” FEBS Letters, vol. 579, no. 27, pp. 6151–6158, 2005.
[22]
L. Aravind, L. M. Iyer, T. E. Wellems, and L. H. Miller, “Plasmodium biology: genomic gleanings,” Cell, vol. 115, no. 7, pp. 771–785, 2003.
[23]
Y. Wang, J. Utzinger, J. Saric et al., “Global metabolic responses of mice to Trypanosoma brucei brucei infection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 16, pp. 6127–6132, 2008.
[24]
A. El Sawalhy, J. R. Seed, J. E. Hall, and H. El Attar, “Increased excretion of aromatic amino acid catabolites in animals infected with Trypanosoma brucei evansi,” Journal of Parasitology, vol. 84, no. 3, pp. 469–473, 1998.
[25]
Y. Chen and G. J. Guillemin, “Kynurenine pathway metabolites in humans: disease and healthy states,” International Journal of Tryptophan Research, vol. 2, pp. 1–19, 2009.
[26]
M. A. Bain, R. Faull, R. W. Milne, and A. M. Evans, “Oral L-carnitine: metabolite formation and hemodialysis,” Current Drug Metabolism, vol. 7, no. 7, pp. 811–816, 2006.
[27]
H. Van Thien, M. T. Ackermans, E. Dekker et al., “Glucose production and gluconeogenesis in adults with cerebral malaria,” QJM, vol. 94, no. 12, pp. 709–715, 2001.
[28]
G. G. Holz, “Lipids and the malarial parasite,” Bulletin of the World Health Organization, vol. 55, no. 2-3, pp. 237–248, 1977.
