Project description DEENESFRITPL Molecular mechanisms underlying Artemisinin resistance in malaria During the blood development stages of the protozoan Plasmodium falciparum, responsible for malaria, the parasite internalises a large part of the host cell cytosol via an endocytic process and digests it in the food vacuole. Recent studies revealed a critical connection of this endocytosis process with the resistance of the parasite to the frontline drug Artemisinin and identified a series of proteins involved in endocytosis, including Kelch13, which is the molecular marker of Artemisinin resistance. The EU-funded MALART project aims to elucidate the molecular mechanisms of the endocytosis, specifically investigate the role of Kelch13 in this process and elucidate the compensatory mechanisms the parasite uses during resistance development. Show the project objective Hide the project objective Objective Blood stages of the protozoan parasite Plasmodium falciparum are responsible for malaria, a disease that kills more than 400'000 people annually. During its development in red blood cells the parasite internalises a large part of the host cell cytosol (hemoglobin) in an endocytic process and digests it in its food vacuole. We recently identified a critical connection of this hemoglobin endocytosis with resistance of the parasite to the current frontline drug Artemisinin, revealing the mechanism of resistance. Artemisinin is activated by hemoglobin degradation products and we found that Artemisinin resistant parasite endocytose less. Using a toolbox of recently established approaches to carry out functional studies in malaria parasites, we identified an entire series of proteins involved in endocytosis that are involved in resistance to Artemisinin. This included Kelch13, the molecular marker of Artemisinin resistance in field samples. This provides us with a unique opportunity (i) to elucidate how these molecules orchestrate endocytosis, a prominent essential process in these parasites that so far is not understood on a molecular level, (ii) to specifically understand the role of Kelch13 in this process and in resistance, and (iii) to elucidate the reason for the fitness cost that is associated with Artemisinin resistance and the compensatory mechanisms the parasite uses to mitigate them. We expect this research program to not only elucidate so far elusive key aspects of the cell biology of this important parasite, but also to identify critical constraints of Artemisinin resistant parasites and possible ways to circumvent ART resistance. Fields of science medical and health scienceshealth sciencesinfectious diseasesmalarianatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biology Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-ADG - ERC ADVANCED GRANT Call for proposal ERC-2020-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Coordinator BERNHARD-NOCHT-INSTITUT FUER TROPENMEDIZIN Net EU contribution € 2 388 242,50 Address Bernhard nocht strasse 74 20359 Hamburg Germany See on map Region Hamburg Hamburg Hamburg Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all BERNHARD-NOCHT-INSTITUT FUER TROPENMEDIZIN Germany Net EU contribution € 2 388 242,50 Address Bernhard nocht strasse 74 20359 Hamburg See on map Region Hamburg Hamburg Hamburg Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
