Global metabolic responses of mice to Trypanosoma brucei brucei infection

Abstract

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 1 H 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

Metabolic, Immune, and Gut Microbial Signals Mount a Systems Response to Leishmania major Infection

“…mansoni infections), indicating that this may be a more general marker of parasitic infection. 16,17 Immunological investigation of the two infected strains confirmed the importance of the innate immune system driving the differential response during early stages of infection, whereby the non-healing model displayed an inherent pro-inflammatory phenotype compared with the self-healing strain. In contrast to published evidence 38 , defining the role of Th1 cytokine IL-12 in the current study proved difficult, not only owing to the variable concentrations measured over the course of infection in both strains, but due to its observed positive association with parasitic load.…”

“…20 A recurrent theme across a range of these parasite-rodent models characterised by metabolic profiling is the association between parasitic infection and an altered host microbiome, as indicated by a set of microbiota-associated metabolites detected in the urine and plasma. 16,17,21 Additionally, results from L. major infection models have demonstrated that germ-free mice failed to heal lesions as compared with their conventional counterparts, despite generating a strong Th1 immune response 22 , which strongly implicates the microbiota in mounting a successful host response to the parasite.…”

“…Such studies on other parasitic infections have conventionally relied on 1 H nuclear magnetic resonance (NMR) spectroscopybased screening of urine and plasma samples, taken from infected rodent hosts for diagnostic biomarker research. 16,17 NMR-based analyses, combined with advances in multivariate statistical tools, have shown to yield highly reproducible data, with correlation of variances (CV's) of major metabolite markers typically below 10%. 18,19 This approach in infection studies has expanded successively to include tissues and, more recently, to combine metrics from both the metabolic and immune system.…”

Physiological regulatory networks: ecological roles and evolutionary constraints

“…This approach will necessitate "-omics" methodologies and/or better sample collection techniques allowing measurement of many parameters from small blood samples. Nuclear magnetic resonance [49], PRN-tailored microarrays, dried blood spots [50], and traditional assays are all potential methods, especially in combination.…”

Clinical Chemistry of Congenic Mice with Quantitative Trait Loci for Predicted Responses to Trypanosoma congolense Infection

“…Groups of 10 mice of each line were sampled immediately before infection and on each of days 3, 9, 17, and 35 during postmortem sample collection, blood was collected by opening the thoracic cavity, removing the sternum, cutting the vena cava caudalis and the aorta cranial to the diaphragm, and collecting all the blood from the thoracic cavity using a pipette; the volume collected was 0.5 to 1 ml. Blood was left for 2 h at room temperature to clot and then stirred and centrifuged at 4,600 ϫ g for 10 min, and the serum was collected.…”