Parasite clearance in malaria: modelling host and therapy mediated parasite control

Abstract

At present malaria is responsible for over half a million deaths annually. Although progress has been made in controlling this disease, the emergence of drug resistant parasite strains has promoted continued investigation into new treatments. The development of new therapies involves deepening our understanding of how an infected host responses to the malaria parasite, and how this response might be improved. Further, it involves improving our understanding of how existing therapies control parasites in a host. In this thesis I seek to better understand both host and therapy mediated control of the malaria parasite.

A central point to understand when investigating host and therapy mediated control of parasites is parasite clearance. This seemingly straightforward concept is confounded by the multiple meanings of the phrase. When a treatment is administered to a patient and parasite numbers decline, this is termed parasite clearance. Parasite numbers can decline after treatment either because a drug stops the parasites producing progeny, or because the host removes parasites more quickly. The latter of these two processes is also called parasite clearance. For clarity we call the overall decline of parasites in a host, overall parasite clearance , and the removal of infected cells by the host, host removal of parasites . In this work I set out to understand how well a host removed parasites during acute infection, and whether this was enhanced during treatment with an antimalarial.

Through the combined use of experimental work and mathematical modelling, I directly measured host removal of parasites, and found that it has a relatively small contribution in both host and therapy mediated control of parasites. Rather, I observed that both host and therapy mediated parasite control greatly reduce parasite proliferation. Finally, by an analysis of a clinical study, I present a new method for assessing drug efficacy at the most critical point in drug treatment. Together, the work I present in this thesis provides some guidance as to how to assess and develop therapies by first providing methods to understand how drugs and host factors control parasites, and then by providing a means to assess such therapies clinically.