Antimalarial Drug Resistance

Abstract

Malaria is the most important parasite species of humans, affecting more than 2.2 billion people, and causing hundreds of millions of clinical cases and around one million deaths every year. Since the 1940s, mass-produced, inexpensive drugs have been available that could effectively treat individuals. However, the evolution of drug-resistance has repeatedly occurred, diminishing the therapeutic efficacy of drugs. The ability of the malaria parasite to quickly develop resistance to therapeutics is the result of its complex life-history. High mutation rates at the cellular level, which provide a means of continually evading the immune system, offer a mechanism for selection of resistance within a host, while interactions between other parasites and their hosts due to variation in transmission and host susceptibility, influence the probability of selection at the population level. A better understanding of the complex interactions between the parasite and its hosts can greatly improve our knowledge of how the evolution of resistance is related to, and impacts, particular life-history traits. This in turn may offer new strategies for controlling the disease. In this dissertation, immunity and within-host competition in malaria and how they can impact the evolution and spread of antimalarial drug resistance are examined. The dissertation is divided into three sections. Section I consists of an introduction to the biology of malaria and mathematical theories for control as well as a review of the ecology and epidemiology of antimalarial drug resistance. In Section II a within-host model of malaria is introduced to explore the mechanisms involved in generating chronic asymptomatic malaria infections. Section III explores the role of superinfection, or the simultaneous infection with multiple genetically distinct clones of the same parasite, and the impact of within-host competition on the evolution of antimalarial drug resistance. Lastly, the impact of heterogeneous biting on antimalarial drug resistance as well as the coevolution of virulence and antimalarial drug resistance are also explored in this section.