Artemisinin-induced Dormancy & Malaria Treatment Failure

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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 infectionsand up to 3 million deaths per year. Artemisinin, and it's derivatives, offer new hope in the effective treatment of malaria.This class of drugs rapidly clears clinical symptoms and parasites, includingthose 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 artemisinintreatment remain susceptible to artemisinin. Our preliminary data suggests that P. falciparum parasites have a unique mechanismto surviveartemisinintreatment:. The drugs induce a dormantring 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 followingtreatment 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 antimalarialdrugs. We will determine if co- administration 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 combinationtherapy. We will supplementthe experimental plan by using mathematical models of the in-host dynamics of P. falciparum infectionsto explore factors that may influence the formation of dormancy and potential ways to reduce parasite recrudescence following treatment withartemisinin. Although conventional resistance to artemisinindrugs 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 artemisininresistance in P. falciparum in our laboratory and will characterize the cellular andmolecular 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 informationregarding 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 developmentof resistance.