Identification of essential components of the thioredoxin and glutathione systems in the human malaria parasite Plasmodium falciparum

• Applicants: Professor Dr. Marcel Deponte; Professor Dr. Jude Marek Przyborski
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558722317

The glutathione and thioredoxin systems of Plasmodium falciparum have been hypothesized to play crucial roles for the blood-stage development of the human malaria parasite. However, although most of the components of both systems have been thoroughly analyzed in vitro, their suitability for rational drug development and their physiological relevance remain predominantly unknown. Exceptions include a few published and unpublished proof-of-principle studies on single components that are summarized in the first section of this grant proposal. With more than a decade of experience in P. falciparum redox research and genetics, we have therefore decided to join the capacities of our laboratories and to switch from single gene and protein analyses to a systematic approach. We aim to (i) systematically identify the essential components of the glutathione and thioredoxin systems for blood-stage development and survival, (ii) decipher if and how both systems act synergistically to ensure parasite survival, and (iii) gain first quantitative data regarding the physiological functions of the different components. The essentiality of the components will be addressed in a combined deletion strategy using a high-throughput and an inducible knockout method. The relevance of the components for redox homeostasis, detoxification processes, drug resistance/susceptibility, and iron metabolism will be analyzed using microscopy as well as established IC50 assays and genetically encoded sensors. A tight collaboration between both laboratories will not only allow us to cover both the glutathione and the thioredoxin systems, but also to cross-validate which components are really suitable candidates for targeted drug development.

• DFG Programme: Research Grants