Whole-body modelling of glucose and lactate dynamics in plasmodium falciparum malaria
Thesis (MSc)--Stellenbosch University, 2020
ENGLISH ABSTRACT: Malaria is the most important parasitic disease affecting man, and continues to threaten public health in developing countries where the disease is endemic. Within the genus Plasmodium, falciparum is responsible for nearly all deaths from malaria worldwide. Two symptoms that are indicative of severe disease and a high risk of mortality are hypoglycaemia (HG - plasma glucose below 2.2 mM) and hyperlactataemia (HL - plasma lactate in excess of 5.5 mM). Though multiple causes of these metabolic comorbidities have been identified qualitatively, there exists a dearth of quantitative evidence that can give a reliable approximation of which aetiological factors have the highest relative contribution to the appearance of these symptoms. Such a quantitative approach would not only improve our understanding of how malaria progresses to severe disease, but also indicate which mechanisms of host-parasite interaction would be the most amenable to targeting by novel antimalarial chemotherapeutics, since new anti-malarial drugs are required to combat the threat of acquired resistance. One tool that has proved useful in the process of identifying novel drug targets is mathematical modelling. In this study we present a whole-body model of host and parasite metabolism that can provide a quantitative assessment of glucose and lactate dynamics in both the healthy and infected state. This model, termed meyer1, combines independently published models describing separate aspects of host and parasite metabolism to yield an in silico platform that is subsequently used to investigate the relative quantitative contribution of the putative causes of HG/HL in the infected state. Results from model simulations and subsequent metabolic control analysis (MCA) indicated that heterogenous parasite sequestration within the microvasculature of organs important in mediating wholebody glucose and lactate homeostasis has the greatest quantitative impact on the appearance of HG/HL; this finding agrees with qualitative statements previously made in literature. In addition, MCA identified several key enzymatic components of parasite and infected erythrocyte glucose metabolism that, if targeted, would yield the greatest contribution in preventing the appearance of hypoglycaemia in severe disease. These include parasite derived new permeability pathways (NPPs), the parasite glucose transporter (PHT1), and parasite hexokinase and phosphofructokinase. In addition to these findings, the final meyer1 model also provides a platform amenable to further development as more clinical data for model parametrisation becomes available. New experimental studies would also assist in providing the data required to supersede the current phenomenological expressions with mechanism-based implementations representing host-parasite interactions mediating microvascular occlusion. This will ultimately lead to more precise identification of novel drug targets at the molecular level that can inhibit the process of parasite sequestration and subsequently help prevent the appearance of HG/HL in severe P. falciparum malaria.
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