Elucidating the Genetic Determinants of Drug Response in Plasmodium falciparum

Plasmodium falciparum malaria remains one of the most lethal infectious diseases despite global efforts toward malaria control and elimination. Antimalarial drugs are an invaluable resource for reducing the burden of malaria but recurring emergence of resistance to frontline treatments is constant threat that will reverse progress that has been made. Our understanding of how the malaria parasites survive exposure to antimalarial drugs is limited in most cases but is essential to understanding how resistance emerges and spreads. A proven method to begin elucidating genetic mechanisms of resistance is by using structured genetic crosses and parents with known phenotypes for clinically relevant traits. In the first study, the underlying genetics of resistance to the antimalarial drug artemisinin is explored utilizing progeny of a genetic cross between NF54, a lab-line originating in West Africa and NHP4026, a recently isolated Southeast Asian parasite clinically resistant to artemisinin. Resistance data is integrated with the genetics of parasites fitness and transcriptional gene regulation for a comprehensive assessment of traits that allow for the emergence of resistance. In the second study, the in vitro assay for quantification of artemisinin resistance is expanded to generate phenotypic data for multiple clinically relevant traits. The improved methodology will provide deeper knowledge of artemisinin resistant parasites identified through surveillance in the field and controlled experiments with lab adapted parasites. In the third study, chromosome regions influencing parasite response to antimalarial drug combinations are detailed using progeny from a genetic cross between MAL31, a recently isolated drug susceptible parasite from Malawi and KH004, a multidrug resistant parasite from Western Cambodia. As artemisinin resistance spread in Africa, the knowledge of genetic background mutations within the African parasite that influence susceptibility to drug combinations currently in clinical traits will help direct future surveillance efforts and patient treatments.