Mathematical modelling to understand the mechanisms of action of antimalarial drugs and host responses in malaria infection.

Abstract

Malaria still remains a major health problem across the globe and is responsible for more than 200 million cases and a half million deaths every year. Currently, artemisinin drugs are the recommended first line therapy for treating malaria, which have partly contributed to the overall reduction in mortality and morbidity caused by malaria infection. However, the rise of artemisinin resistant malaria parasites is stalling the progress in controlling this disease. Hence, there is a compelling need for new antimalarial drugs and an effective vaccine. Successful immunological and drug interventions must control infection, which could involve the direct removal of circulating parasites and/or blockage of new infections. In this thesis, I investigate the mechanisms of action of existing and novel antimalarial drugs and host responses in controlling of infection. I do this by developing mathematical models and combining them with data to directly measure the rate of parasite clearance, the rate of parasite replication and maturation through their life-cycle in malaria infection. I then utilise these approaches to explore how parasite clearance, maturation and replication are altered by various drugs, parasite gene knockdowns and host-immune interventions. Key insights from this work include, identifying that the rate of host removal of parasites cannot easily be increased from the basal rate. However, I identify two antimalarials (a novel and candidate agent), which induce rapid removal of parasites. However, most drugs and host responses control infection by directly killing or impairing parasites. Through this work I have also identified that a parasite protein, responsible for transporting other proteins to the surface of the red blood cell, is surprisingly not required for parasites to avoid host removal, but is important in parasite development. More generally, I observe that parasite maturation is perturbed by many interventions, suggesting delayed development is a generic parasite stress phenotype. Collectively, the work presented here greatly improves our understanding of host, parasite and drug interactions that govern parasite survival and control of infection by providing better tools to investigate host responses and the mechanisms of action of antimalarial drugs during infection.