MALARTRES

Malaria is a major health problem in tropical and subtropical areas with an unacceptable toll of more than 1 million deaths each year and represents a significant risk to millions of travelers. In 2001, WHO recommended to use artemisinin derivatives (ARTs) in combination with a partner drug as first-line for Plasmodium falciparum treatment. To date almost all malaria-endemic countries have since changed their treatment policy accordingly leading to a 31% reduction in global malaria deaths for the last 10 years. However, since 2004, a major threat has emerged in Western Cambodia where clinical efficacy of ARTs has markedly decreased, with a delayed parasite clearance rate and high recrudescence rates in the following weeks. Artemisinin-resistant Plasmodium falciparum malaria parasites are now reported in all the Greater Mekong region (Cambodia, Vietnam, Thailand & Myanmar). Resistance to ARTs emerges at a time when no in vitro methodology or molecular or biochemical predictive markers exist to detect and study it. Moreover, there is currently no group of drugs that can replace artemisinins. The general objective of this proposal is to better understand P. falciparum resistance to ARTs and to develop new diagnostic and therapeutic tools to fight ARTs-resistant parasites. This innovative and ambitious project is proposing to characterize the in vitro quiescence phenotype induced by artemisinin resistance (Objective 1). This work is based on a major tool: the strain F32-ART, the only reported stable and highly artemisinin-resistant strain of P. falciparum that can be cultured in vitro, and able to survive 7000-fold the dose of ARTs that kills sensitive parasite strains. This strain permitted to Partners 1 & 2 to make a breakthrough by demonstrating that artemisinin resistance involves young stages which survive toxic effect of the drug through temporary growth arrest. Very recently, we have participated to show that quiescence is not only an in vitro phenomenon but also the mechanism of resistance to ARTs of malaria isolates from patients in Asia. F32-ART strain is thus a perfect model to study quiescence in the malaria parasite. Virtually nothing is known to date about this quiescence phenomenon in P. falciparum such as the mechanisms by which F32-ART parasites survive, and pathways involved in induction, maintenance and exit from quiescence. Analysis of ART-resistance phenomenon is an essential scientific challenge as quiescence affects a subset of young stages parasites which to date cannot be isolated from the rest of the parasite population. Technology of labeled parasites F32-ART GFP-luciferase developed by Partner 3 will be a major asset to meet this goal. The lack of understanding the molecular basis of artemisinin resistance is a major roadblock for identification and monitoring of isolates with decreased sensitivity to ARTs in the field. Construction by Partner 3 of parasites transfected by targeted genes selected by sequencing F32-ART/F32-Tanzania whole genome should fulfill this gap. The success of this project should deliver tools for epidemiological monitoring of artemisinin-resistant parasites (Objective 2). Moreover it is urgent to find therapeutic solutions to circumscribe these resistant parasites with selection of compounds or drug combinations active against ART-resistant parasites (Objective 3). From a fundamental point of view, this project should help to better understand this new mechanism of parasite resistance, namely quiescence. From a practical point of view, it should determine molecular makers for monitoring artemisinin resistance and find active molecules against ART-resistant parasites.