Unravelling mechanisms of stage conversion in malaria parasites

Malaria remains a major global health threat with over 200 Mio cases and 400’000 deaths annually, the majority of them due to infection by Plasmodium falciparum. Malaria elimination depends on strategies to eliminate the parasite reservoir and prevent its onward transmission to mosquitoes. Production of transmission stages (or gametocytes) is variable across parasite species and strains, conditions as well as being environmentally sensitive. Studies in P. falciparum revealed that epigenetic mechanisms regulate the plasticity in gametocyte production in response to changes in the within-host environment. Specifically, we discovered that limiting levels of the serum phospholipid LysoPC are translated into transcriptional upregulation of alternative metabolic pathways for phosphatidylcholine biosynthesis and the transcription factor ap2-g. Epigenetic activation of the transcription factor, ap2-g in turn triggers the transcriptional program for sexual development. LysoPC is an immune metabolite and reduction in systemic LysoPC levels is the result of inflammation, for example due to acute malaria. How exogenous LysoPC levels regulate both, expression of metabolic enzymes and the epigenetic switch underlying stage conversion in the parasite is the subject of the current proposal.