Reduced susceptibility of the human malaria parasite Plasmodium falciparum to the first line drug artemisinin and derivatives (ART) has spread in South East Asia and now is also spreading in Africa where the highest burden of malaria lies. While ART is typically given with a partner drug, resistance to partner drugs also exists, together jeopardising treatment and the general goal of reducing malaria-related deaths. Most cases with reduced susceptibility to ARTs contain mutations in a gene of the parasite encoding the protein Kelch13. In previous work we and others showed that Kelch13 is needed for the parasite to endocytose cytosol from the host red blood cell (consisting almost exclusively of haemoglobin). The parasite grows within human red blood cells and “feeds” on the host cell cytosol by an endocytic process (taking up host cell cytosol in membrane bound packets formed at the interface to the host cell) and digests the content in its food vacuole. This is critical for parasite survival, firstly, to obtain amino acids from digested haemoglobin and secondly, to make room for growth in the host cell. However, the iron containing part of haemoglobin can not be digested and is stored in the food vacuole of the parasite. This degradation product is known to activate ART, which only then becomes toxic for the parasite. In parasites where Kelch13 is less active, such as in the mutated forms found in resistant parasites, less ART is activated, reducing the susceptibility of the parasite to this drug. However, it will also reduce the amino acids taken in, hence imposing a fitness cost on the parasite.
All of this highlighted that we
1. do not understand the endocytosis process in the parasite: how are host cell cytosol containers formed, which proteins are involved (K13 one of the first molecular players), how is endocytosis regulated, does it respond to nutrient cues, is it connected to developmental switches and speed of growth? (part 1)
2. do not know how Kelch13 influences endocytosis as this protein is not a typical vesicle trafficking protein (part 2)
3. do not know whether the fitness cost limits the level of resistance the parasite can achieve and does this impose constraints and compensatory responses in the parasite: ART resistance is only a partial resistance and it is unclear if parasites could become more resistant. Finally, the impact of the fitness cost on the parasite and potential constraints this imposes on the ART resistant parasites and how this potentially could be exploited is unclear (part 3)
In this project we are addressing these questions by unravelling the fundamental, so far poorly understood vesicle trafficking pathway that is critical for ART resistance, thereby bridging basic cell biology and a topic of high clinical relevance.
