MALSWITCH - Uncovering the Mechanisms Behind Adaptive Gene Expression Switching in Malaria Parasites

01.01.2023 bis 31.12.2026

The malaria-causing parasite Plasmodium falciparum has evolved a strategy of clonally variant gene expression to control essential biological processes like antigenic variation and sexual commitment during its persistent blood-stage infection of the human host. Heritable epigenetic silencing of the underlying specialized gene families ensures the limited expression of only a subset of these genes at any time. Switching the expression of individual clonally variant genes enables the parasite to rapidly adapt to changes in its environment, evade the immune system and switch its cell cycle to the development of mosquito-transmissible gametocyte stages. Expression switching of these clonally variant genes therefore represents a key strategy for parasite survival and underlies the evolutionary success of this deadly pathogen. Despite decades of research, the molecular mechanisms coordinating this adaptive gene expression switching are not understood. In my recent research, I developed a unique experimental tool, which for the first time allows the conditional expression switching of endogenous genes in the parasite. I will combine this system with novel CRISPR/Cas derived methodology and proximity-based labelling approaches to deliver the first systematic identification and characterization of the molecular mechanisms controlling epigenetic gene expression switching. The experiments outlined in the proposal will reveal the core of the molecular machinery underlying this fundamental process and elucidate regulatory mechanisms that allow the parasite to translate environmental signals into adaptive switching of clonally variant genes. This will transform our understanding of the molecular mechanisms driving adaptation of this deadly parasite and in the long run might contribute to the design of intervention strategies that P. falciparum is unable to adapt to.