Artemisinin-induced Dormancy & Malaria Treatment Failure

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DESCRIPTION (provided by applicant): The development and spread of drug resistance in malaria parasites has become a major obstacle in the treatment and control of a disease that causes approximately 300 million infections and up to 3 million deaths per year. Artemisinin, and its derivatives, offer new hope in the effective treatment of malaria. This class of drugs rapidly clears clinical symptoms and parasites, including those that are multi-drug resistant. Unfortunately, when these drugs are used alone, > 40% of cases will produce recrudescent infections. Unlike recrudescence following treatment by other anti-malarial drugs, parasites appearing after artemisinin treatment remain susceptible to artemisinin. Our preliminary data suggests that P. falciparum parasites have a unique mechanism to survive artemisinin treatment: The drugs induce a dormant ring stage parasite in which growth is arrested for several days before the parasites recover and grow normally. This project aims to investigate the rate at which dormant parasites develop and recover following treatment with various artemisinin derivatives in vitro. In addition the duration of dormancy will be estimated. The role of dormancy in vivo will be investigated in an animal model. Physiological, cellular and molecular characterization of the dormant parasites will be performed to identify determinants/markers for dormancy and establish the mechanism(s) by which dormancy occurs. Artemisinin combination therapy (ACT) has been strongly recommended by WHO as a strategy to reduce recrudescence and to combat widespread resistance to all other cheap, available antimalarial drugs. We will determine if coadministration of drugs is effective in killing dormant parasites, or if the elimination half-life of the combination drug is the key factor in the success of combination therapy. We will supplement the experimental plan by using mathematical models of the in-host dynamics of P. falciparum infections to explore factors that may influence the formation of dormancy and potential ways to reduce parasite recrudescence following treatment with artemisinin. Although conventional resistance to artemisinin drugs has not yet been observed in the field, experiences with all other antimalarial drugs indicate the significant risk of parasites developing resistance to artemisinin drugs. We have developed artemisinin resistance in P. falciparum in our laboratory and will characterize the cellular and molecular mechanism(s) associated with resistance. These include transcriptional, translational/post-translational changes and mutations in potential drug transporters. This component of the project will elucidate possible mechanisms by which parasites develop resistance to this class of drug and the role of artemisinin-induced dormancy in the process. The results of this project will provide valuable information regarding the mechanisms of treatment failure for artemisinin drugs. The results will aid the formulation of optimal ACT regimens, improved treatment outcomes for malaria patients and defined strategies of preventing the development of resistance.