Last Updated: 20/10/2022
Cellular basis of Artemisinin resistance in malaria parasites
Objectives
To elucidate the molecular mechanisms of endocytosis, specifically investigate the role of Kelch13 in this process and find out the compensatory mechanisms the parasite uses during resistance development.
Specific objectives:
(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.
(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.
Bernhardt Nocht Institute for Tropical Medicine (BNITM), Germany
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. It was recently identified thaat there is 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 it was found that Artemisinin resistant parasite endocytose less. Using a toolbox of recently established approaches to carry out functional studies in malaria parasites, an entire series of proteins involved in endocytosis were identified which are involved in resistance to Artemisinin. This included Kelch13, the molecular marker of Artemisinin resistance in field samples.
Dec 2021 — Nov 2026
$2.7M
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