Mota, M. M. | bioRxiv Science

bioRxiv2022

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

For Plasmodium falciparum, the most widespread and virulent malaria parasite that infects humans, persistence depends on continuous asexual replication in red blood cells, while transmission to their mosquito vector requires asexual blood-stage parasites to differentiate into non-replicating gametocytes. This decision is controlled by stochastic de-repression of a heterochromatin-silenced locus encoding PfAP2-G, the master transcription factor of sexual differentiation. The frequency of pfap2-g de-repression was shown to be responsive to extracellular phospholipid precursors but the mechanism linking these metabolites to epigenetic regulation of pfap2-g was unknown. Here 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 parasites pathway for de novo phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of SAM for de novo phosphatidylcholine synthesis impairs maintenance of the histone methylation responsible for silencing pfap2-g, increasing the frequency of derepression and sexual differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/476397v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@5e2c69org.highwire.dtl.DTLVardef@b5a7d6org.highwire.dtl.DTLVardef@1e118aorg.highwire.dtl.DTLVardef@1191a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2021

A spatiotemporally resolved single cell atlas of the Plasmodium liver stage

Malaria infection involves an obligatory, yet clinically silent liver stage1,2. Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis3, but the effects of hepatocyte zonation on parasite development have not been molecularly explored. Here, we combine single-cell RNA sequencing4 and single-molecule transcript imaging5 to characterize the hosts and parasites temporal expression programs in a zonally-controlled manner for the rodent malaria parasite Plasmodium berghei ANKA. We identify differences in parasite gene expression in distinct zones, and a sub-population of periportally-biased hepatocytes that harbor abortive infections associated with parasitophorous vacuole breakdown. These abortive hepatocytes up-regulate immune recruitment and key signaling programs. They exhibit reduced levels of Plasmodium transcripts, perturbed parasite mRNA localization, and may give rise to progressively lower abundance of periportal infections. Our study provides a resource for understanding the liver stage of Plasmodium infection at high spatial resolution and highlights heterogeneous behavior of both the parasite and the host hepatocyte.

genomics↗