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Cellular basis of Artemisinin resistance in malaria parasites

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.

Call for proposal

ERC-2020-ADG
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Host institution

BERNHARD-NOCHT-INSTITUT FUER TROPENMEDIZIN
Address
Bernhard Nocht Strasse 74
20359 Hamburg
Germany
Activity type
Research Organisations
EU contribution
€ 2 388 242,50

Beneficiaries (1)

BERNHARD-NOCHT-INSTITUT FUER TROPENMEDIZIN
Germany
EU contribution
€ 2 388 242,50
Address
Bernhard Nocht Strasse 74
20359 Hamburg
Activity type
Research Organisations