Elucidating mechanisms for artemisinin-induced dormancy in Plasmodium falciparum

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Project Summary Among the numerous problems plaguing the malaria elimination efforts is the emergence and spread of drug resistance in P. falciparum. Resistance to artemisinin has led to reduced efficacy of artemisinin combination therapy (ACTs) and ultimately selection of resistance to the partner drugs (e.g., piperaquine). Clearly the threat of multi-drug resistant malaria is as important today as it has ever been, with the precious gains in malaria control threatened by the potential for the spread of P. falciparum strains that are resistant to all currently available treatment drugs. Resistance to artemisinin is not the only factor responsible for treatment failures. Even before artemisinin resistance emerged, recrudescent infections were commonly observed when patients were treated with artemisinin derivatives alone. In some studies, even 5-7 days of treatment with artesunate alone led to ~10% recrudescent infections. The underlying cause of these recrudescent infections has been attributed to the unique ability of artemisinin to arrest the growth of ring stages of P. falciparum. These dormant rings can persist for days to weeks before recovering and growing normally to cause a recrudescent infection. Our published and preliminary data led us to the hypothesis that selection of artemisinin resistance is a two-step process in which the initial responses of the parasite to artemisinin drug pressure is an enhanced dormancy phenotype that confers increased tolerance to drug; subsequently resistance conferring mutations occur (e.g., K13). In Aim 1 we will overexpress genes in a novel chromosome 10 copy number variant we identified in independently derived artemisinin-resistant clones. In Aim 2 will use novel high content imaging assays to quantify enhanced dormancy recovery phenotypes in artemisinin-resistant versus -susceptible P. falciparum. The results of these studies will provide evidence for the molecular basis of recovery from artemisinin-induced dormancy and possibly reveal new mechanisms of resistance to artemisinin.