Abstract

Malaria remains one of the major infectious diseases worldwide, responsible for over 240 million cases and more than 600,000 deaths each year. Mature gametocytes, the sexual stages of Plasmodium falciparum, are the only forms capable of ensuring parasite transmission from humans to Anopheles mosquito and thus represent a key target for malaria elimination. These stages constitute a bottleneck in the parasite life cycle, but their low metabolic activity makes them difficult to target with current treatments. To persist for several weeks in circulation, gametocytes remodel the mechanical properties of their host erythrocytes. Mature gametocyte-infected erythrocytes (GIEs) are more deformable and less permeable than immature GIEs, which allows them to escape splenic retention and hemolysis. Altering these mechanical properties could therefore promote their clearance and limit transmission to the vector.  

In this context, the objective of this thesis was to explore the molecular mechanisms that regulate the mechanical properties of GIEs. While previous work has established that mechanical properties are regulated by dynamic phosphorylation events, we investigated the role of the parasite phosphatase PfPP1 in these mechanisms. Our results revealed that PfPP1 is involved in regulating both GIE deformability and permeability through PKA-dependent dephosphorylation, and also plays a role in gametogenesis via the cGMP pathway.

In a second part, we examined the mode of action of tadalafil, a phosphodiesterase inhibitor that increases GIE rigidity and permeability in vitro and promotes their clearance from bloodstream in vivo in a humanized mouse model. We also show that this effect depends on the cGMP-PfPKG pathway in both sexual and asexual stages and also appears to involve PfCK2. To better understand its mechanism of action, we investigated the phosphorylation changes induced by tadalafil in GIEs. This analysis revealed a new player, the protein PfEPF1 (Exported Protein Family 1), capable of increasing GIE rigidity.

Altogether, this work deepens our understanding of the signaling pathways that regulated the mechanical properties of P. falciparum GIEs. It highlights potential therapeutic targets for the development of transmission-blocking strategies, thereby contributing to efforts to limit parasite propagation.