Metabolic competition between lipid metabolism and histone methylation regulates sexual differentiation in human malaria parasites.

Abstract

Like most pathogens, malaria parasites balance persistence in the current host with transmission to the next. For Plasmodium falciparum, the most widespread and virulent human malaria parasite, persistence depends on continuous asexual replication in red blood cells while transmission requires differentiation into non-replicating gametocytes, the male and female cells able to infect the mosquito vector. This developmental decision is controlled via stochastic derepression of a heterochromatin-silenced locus encoding the transcription factor PfAP2-G, which acts as the master switch for sexual differentiation. Recent work showed that the frequency of pfap2-g derepression is responsive to extracellular levels of phospholipid precursors. However, the regulatory mechanisms linking these metabolites to epigenetic regulation of pfap2-g was hitherto unknown. Using chemical, metabolomic, and genetic approaches, we show that this response is mediated by metabolic competition for the methyl donor S-adenosylmethionine between histone methyltransferases and phosphoethanolamine methyltransferase, a critical enzyme in the parasite pathway for de novo phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of S-adenosylmethionine for de novo synthesis of phosphatidylcholine results in a decrease in histone methylation marks that mediate silencing of pfap2-g, thereby up-regulating its transcription and increasing the frequency of sexual differentiation. Our findings reveal a key connection between metabolite utilization and gene expression in malaria parasites that forms the mechanistic link between phosphatidylcholine metabolism and the frequency of sexual commitment.

Host cell maturation modulates parasite invasion and sexual differentiation in Plasmodium berghei

“…This unknown serum factor may act as an environmental sensor and activator of sexual commitment, after it is imported in and/or metabolized by reticulocytes only. A recent study suggests that limiting parasite S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels results in ap2-g activation and sexual commitment both in P. falciparum and P. berghei (47). It is conceivable that the factor triggering sexual commitment in nutrient-rich environments is associated with SAM/SAH metabolism.…”

Plasmodium falciparum S-Adenosylmethionine Synthetase Is Essential for Parasite Survival through a Complex Interaction Network with Cytoplasmic and Nuclear Proteins

“…It has been postulated that under reduced lysoPC conditions, the parasites need to utilize SAM to generate PC, and, in consequence, less SAM could be used to repress the ap2-g locus via histone methylation [ 44 ]. In fact, a new report [ 45 ] confirmed that lack of lysoPC in the medium results in increased Pf PMT expression and decreased SAM levels in P. falciparum , while Pf PMT deficiencies increase intracellular SAM levels and repress sexual commitment.…”

Variation in Plasmodium falciparum sexual commitment rates and responses to environmental modification

“…It will be important to understand if there is intraspecific variation in natural regulation of GDV1 expression, particularly the control of gene-silencing antisense transcripts [13], and investigate the potential influence of naturally-occurring cis-variation at the sub-telomeric locus on chromosome 9 [33, 39, 44] distinct from the deletions disrupting function in some cultured lines [12, 36, 37, 45]. An important new insight into the effect of available choline has just been reported, indicating that sexual commitment is affected by competition between histone methyltransferases (involved in ap2-g gene silencing) and phosphoethanolamine methyltransferase (involved in de novo synthesis of phosphatidylcholine when choline availability is low) for the methyl donor S-adenosylmethionine, which could have implications for future studies on inter-isolate variation in rates of sexual commitment [32]. Investigation of parasites in natural populations requires assay precision and experimental replication to be considered where possible alongside statistical power from increased numbers of clinical samples, whether for candidate gene investigations or larger scale scanning for associations with unlinked genomic variation in parasite populations [46].…”

“…An increase in gametocytogenesis may be triggered by cellular stress involving redox perturbation [26, 27], by adding low doses of the antimalarial artemisinin at the early trophozoite growth stage [28], or by adding parasite-conditioned culture medium [29] or extracellular vesicles from such medium [30]. Notably, gametocyte conversion rates in cultured lines are suppressed by lysophosphatidylcholine (LysoPC) within serum, or by adding choline as a supplement in serum-free medium [31, 32]. In a study of parasite development during the initial ex vivo cycle cultured from clinical samples in Ghana, the proportions of parasites showing conversion to gametocytes correlated positively with level of parasitaemia and negatively with concentration of LysoPC in plasma of patients, supporting a hypothesis that developmental responses to metabolic stress may occur during natural infections [33].…”

“…An increase in gametocytogenesis may be triggered by cellular stress involving redox perturbation [26,27], by adding low doses of the antimalarial artemisinin at the early trophozoite growth stage [28], or by adding parasiteconditioned culture medium [29] or extracellular vesicles from such medium [30]. Notably, gametocyte conversion rates in cultured lines are suppressed by lysophosphatidylcholine (LysoPC) within serum, or by adding choline as a supplement in serum-free medium [31,32].…”