Malaria remains a major public health problem despite significant eradication efforts, killing more than half a million people every year and putting nearly half the world’s population at risk. It is caused by unicellular eukaryotic Plasmodium parasites, which are transmitted via mosquito bites and replicate through a complex life cycle with several distinct stages involving both the vertebrate and the insect hosts.

During their life cycle, Plasmodium parasites must continually adapt to changing environments for successful proliferation and transmission. However, how they sense their surroundings to adapt their development remains a mystery, as they lack known receptors but can yet respond to extracellular signals.

In this thesis, I investigated how extracellular signals modulate cGMP homeostasis during transmission of Plasmodium gametocytes. Our findings show that a protein UGO (Unique GC Organizer) plays a crucial role in upregulating activity of the guanylyl cyclase GCα in response to extracellular cues. We also demonstrate that a signaling linking factor (SLF) is required for full basal GCα activity and optimal upregulation, and identified temperature-dependent epistatic interactions among two phosphodiesterases, PDEα and PDEδ.

Furthermore, we could show that premature activation of gametocytes at 37°C leads to abortive gametogenesis. A medium-throughput screening of approximately 4,000 compounds in P. berghei gametocytes identified several molecules capable of activating gametocytes by phenocopying XA mode of action, with the antidepressant sertraline showing particularly promising results. Interestingly, sertraline also shows a fast-killing activity against P. falciparum asexual blood stages in vitro. While the mode of action of sertraline in asexual blood stages remains to be identified, characterizing its target can pave the way for the development of novel multistage anti-Plasmodium molecules.