Mathematical modelling of hypoglycaemia and lactic acidosis in the bloodstream of Plasmodium berghei infected rats: a feasibility study

Walters, Nicolas (2016-03)

Thesis (MSc)--Stellenbosch University, 2016


ENGLISH ABSTRACT : Needless prescription and overuse of anti-microbial compounds served as a catalyst for the evolution and rise of multiple drug resistant pathogens, one of humanities greatest threats in the anti-biotic era. Resistance to our last line of defence drugs for malaria, a disease that reportedly caused the deaths of more than half a million people in 2013, is being reported in South-east Asia, necessitating the need for a novel high throughput method of anti-malarial drug development. Advances in the field of systems biology and further development of metabolic control analysis, could be used to identify drug targets from metabolic models. The purpose of this project was to investigate the feasibility of creating a whole body model of rats infected with P. berghei. To assess the feasibility, a initiatory glycolytic model was constructed and the possibility of modelling the change in blood parameters over the course of a malarial infection was investigated. Wistar rats were infecting with P. berghei, ANKA strain, and blood parameters, including blood glucose and lactate concentration, haematocrit and parasitemia was measured and the relationship between the parameters evaluated. Furthermore, pulse experiments were performed to analyse the possibility of modelling the homeostatic potential of the rat. Microscopy and enzymatic glucose and lactate concentration determinations proved to be reliable and accurate methods to measure blood parameters. In addition, a relationship between parasitemia and the other blood parameters could be quantified, providing evidence that the physiological changes during malarial infection could be modelled. The glycolytic enzymes were liberated from the parasites and biochemically characterized. The kinetic parameters obtained from the characterization were subsequently used to construct a glycolytic model. Steady state concentrations predicted by the preliminary model fall within physiological ranges, indicating that the model construction is feasible. In conclusion, the results from the experiments, biochemical characterization of the glycolytic enzymes isolated from P. berghei and preliminary model construction of the glycolytic pathway supports the feasibility of creating a complete whole body model, warranting further investigation.

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