Malaria is a major health problem worldwide, with over 250 million people becoming infected and up to 1 million deaths annually. Artemisinin and derivative compounds provide rapid relief of malaria symptoms with faster clearance of parasitemia than any other drugs. Despite the remarkable activity and broad stage specificity of artemisinin drugs, between 10-40 percent of patients experience recrudescence of the infection 7 to 28 days post-treatment. The recrudescent parasites remain susceptible to artemisinin in vitro, suggesting that the high frequency of treatment failure is not due to conventional resistance mechanisms. We have investigated recrudescence following exposure to artemisinin in vitro and in vivo. We have shown that ring stage parasites exposed to artemisinin drugs become dormant and persist in this arrested state for hours to days in vitro before recovering and resuming cell cycle progression. Furthermore, we have shown that both artemisinin sensitive and resistant parasites enter dormancy following exposure to drug, yet resistant lines require elevated drug concentrations to induce dormancy and subsequently recrudesce earlier in vitro. We hypothesize that the formation of dormant parasites during artemisinin treatment is not only a key factor in the high rates of treatment failure and recrudescence of infection, but also in the development of resistance to the artemisinin class of drugs. The long-term objective of these studies is to define the novel regulatory features of cell cycle arrest and dormancy in Plasmodium falciparum, and identify the essential factors involved in the key checkpoints that regulate it. In these studies, we will characterize the transcriptional regulatory processes of Plasmodium falciparum dormancy, identify parasite genes essential for cell cycle progression through stage-specific transcriptional drug response analyses, and elucidate the metabolic signatures of resistant parasites in drug-induced arrest. This novel research approach is innovative in two ways in that we will be functionally characterizing drug-induced dormancy, as well as simultaneously uncovering potential new drug targets and pathways. This project will enable us to grasp a better understanding of the mechanisms of parasite drug evasion strategies, and allow us to design better drugs to treat and prevent this disease.
Artemisinin drugs are critical as they serve as the major tool for treating multidrug resistant malaria. Unfortunately, artemisinin resistance has emerged in Southeast Asia;therefore, a better understanding of the mechanism(s) by which these parasites avoid the effects of these drugs is required. The goals of this project are to apply innovative approaches to better characterize drug-induced dormancy in malaria, and to discover novel metabolic signatures of resistant parasites that may serve as the basis for new drugs and diagnostics development.