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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Global metabolic responses of mice to Trypanosoma brucei brucei infection
*Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom; Departments of Public Health and Epidemiology and Medical Parasitology and Infection Biology, Swiss Tropical Institute, CH-4002 Basel, Switzerland; Department of Biomedicine/Endocrinology and ¶Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland; and ||Office of Population Research, Princeton University, Princeton, NJ 08544
Contributed by Burton H. Singer, February 25, 2008 (received for review November 9, 2007)
Human African trypanosomiasis (HAT) is transmitted by tsetse flies and, if untreated, is fatal. Treatment depends on infection stage, and early diagnosis is crucial for effective disease management. The systemic host biochemical changes induced by HAT that enable biomarker discovery or relate to therapeutic outcome are largely unknown. We have characterized the multivariate temporal responses of mice to Trypanosoma brucei brucei infection, using 1H nuclear magnetic resonance (NMR) spectroscopic metabolic phenotyping of urine and plasma. Marked alterations in plasma metabolic profiles were detected already 1 day postinfection. Elevated plasma concentrations of lactate, branched chain amino acids, and acetylglycoprotein fragments were noted. T. brucei brucei-infected mice also had an imbalance of plasma alanine and valine, consistent with differential gluconeogenesis (parasite)-ketogenesis (host) pathway counterflux, involving stimulated host glycolysis, ketogenesis, and enhanced lipid oxidation in the host. Histopathologic evidence of T. brucei brucei-induced extramedullary hepatic hemopoiesis, renal interstitial nephritis, and a provoked inflammatory response was also noted. Metabolic disturbance of gut microbiotal activity was associated with infection, as indicated by changes in the urinary concentrations of the microbial co-metabolites, including hippurate. Concluding, parasite infection results in multiple systemic biochemical effects in the host and disturbance of the symbiotic gut microbial metabolic interactions. Investigation of these transgenomic metabolic alterations may underpin the development of new diagnostic criteria and metrics of therapeutic efficacy.
diagnosis | metabonomics | NMR spectroscopy | trypanosomiasis
Present address: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0801777105/DCSupplemental.
**To whom correspondence may be addressed. E-mail: elaine.holmes{at}imperial.ac.uk or singer{at}princeton.edu
© 2008 by The National Academy of Sciences of the USA
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