A mechanistic model quantifies artemisinin-induced parasite growth retardation in blood-stage Plasmodium falciparum infection

Falciparum malaria is a major parasitic disease causing widespread morbidity and mortality globally. Artemisinin derivatives---the most effective and widely-used antimalarials that have helped reduce the burden of malaria by 60% in some areas over the past decade---have recently been found to induce growth retardation of blood-stage Plasmodium falciparum when applied at clinically relevant concentrations. To date, no model has been designed to quantify the growth retardation effect and to predict the influence of this property on in vivo parasite killing. Here we introduce a mechanistic model of parasite growth from the ring to trophozoite stage of the parasite's life cycle, and by modelling the level of staining with an RNA-binding dye, we demonstrate that the model is able to reproduce fluorescence distribution data from in vitro experiments using the laboratory 3D7 strain. We quantify the dependence of growth retardation on drug concentration and demonstrate the model's utility as a platform to propose experimentally-testable mechanisms of growth retardation. Furthermore we illustrate that a drug-induced delay in growth may significantly influence in vivo parasite dynamics, demonstrating the importance of considering growth retardation in the design of optimal artemisinin-based dosing regimens.
Comment: 44 pages, 20 figures (including 8 supplementary figures), 8 tables (including 6 supplementary tables)