Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum

Abstract

SummaryTransmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.

Probing Plasmodium falciparum sexual commitment at the single-cell level

“…To capture the transcriptional profile of sexual commitment, cells were exposed to a pulse of defined medium lacking LysoPC (−SerM), as described previously 16 . At three time points after LysoPC depletion, 336 individual cells (and 48 control cells in the presence of LysoPC; −SerM/LysoPC) were collected by flow sorting and snap-frozen prior to being processed for DGE ( Figure 1a and Supplementary Figure 1).…”

“…Initial analysis of gene expression in individual sexually committed cells using conditional AP2-G knock-down provided a first transcriptional signature upon AP2-G activation 15 . We have recently demonstrated that availability of the host-derived phospholipid lysophosphatidylcholine (LysoPC) acts as an environmental sensor for the regulation of sexual commitment in P. falciparum 16 . We have shown that LysoPC is the major building block for phosphatidylcholine biosynthesis in the parasite, and its depletion results in the induction of a compensatory metabolic response and triggers AP2-G activation and sexual commitment in a large part of the parasite population.…”

“…We have shown that LysoPC is the major building block for phosphatidylcholine biosynthesis in the parasite, and its depletion results in the induction of a compensatory metabolic response and triggers AP2-G activation and sexual commitment in a large part of the parasite population. This observation was facilitated through development of a highly controlled and quantitative in vitro assay to induce gametocyte formation 16, 17 . Here we apply this assay to define the transcriptional signature of individual cells at different stages during sexual commitment and validate key findings experimentally.…”

Probing Plasmodium falciparum sexual commitment at the single-cell level

“…Malaria remains a major global health issue, with roughly 200 million infections and more than 400,000 fatal cases caused by Plasmodium falciparum each year 1 . Despite decades of disease-control and elimination efforts, P. falciparum persists in many geographic regions, highlighting the adaptability of this parasite to changing environments.…”

Sex in Plasmodium falciparum: Silence Play between GDV1 and HP1

“…Recent studies on lysophosphatidylcholine and sexual differentiation are an initial step in this direction [10]. …”