Plasmodium falciparum sexual differentiation in malaria patients is associated with host factors and GDV1-dependent genes

Abstract

Plasmodium sexual differentiation is required for malaria transmission, yet much remains unknown about its regulation. Here, we quantify early gametocyte-committed ring (gc-ring) stage, P. falciparum parasites in 260 uncomplicated malaria patient blood samples 10 days before maturation to transmissible stage V gametocytes using a gametocyte conversion assay (GCA). Seventy six percent of the samples have gc-rings, but the ratio of gametocyte to asexual-committed rings (GCR) varies widely (0–78%). GCR correlates positively with parasitemia and is negatively influenced by fever, not hematocrit, age or leukocyte counts. Higher expression levels of GDV1-dependent genes, ap2-g , msrp1 and gexp5 , as well as a gdv1 allele encoding H 217 are associated with high GCR, while high plasma lysophosphatidylcholine levels are associated with low GCR in the second study year. The results provide a view of sexual differentiation in the field and suggest key regulatory roles for clinical factors and gdv1 in gametocytogenesis in vivo.

Dissecting the role of PfAP2-G in malaria gametocytogenesis

“…MSRP1 has homology to MSP7, a known invasion protein, but little is known about it beyond its dispensability for asexual growth 33 . Multiple datasets show that msrp1 is upregulated in committed cells 17,19,20,[34][35][36] . Crucially, msrp1 is-like ap2-g-highly upregulated in field isolates compared to laboratory strains, suggestive of a possible role in gametocytogenesis 37 .…”

“…Our data suggest a model in which PfAP2-G and PfAP2-I cooperate to direct a committed-schizont specific transcriptional program that includes upregulation of many invasion genes. In a committed schizont, many invasion transcripts are slightly upregulated, with msrp1 alone highly upregulated during commitment across multiple datasets 13,17,19,20,[34][35][36] . One reason for this distinct invasion-related transcriptional program may be to allow committed merozoites to utilize a different invasion pathway than asexual merozoites.…”

“…HP1-mediated silencing of ap2-g is a ubiquitous feature of its regulation as it has recently been demonstrated across a range of Plasmodium species 16 . In P. falciparum, the protein GDV1 is responsible for removing HP1 from the ap2-g locus and so is also an important positive regulator of commitment [17][18][19] . Although some aspects of the regulation of PfAP2-G itself have now been explored, relatively little is known about how PfAP2-G directs the sexual commitment transcriptional program and which genes are involved.…”

Exposure to artemisinin at the trophozoite stage increases sexual conversion rates in the malaria parasite Plasmodium falciparum

“…Recent research has established that depletion of the human serum lipid lysophosphatidylcholine (LysoPC) underlies the stimulation of sexual conversion by high asexual parasitemia or spent medium, providing the first mechanistic insight into 85 how environmental conditions can influence the rate of sexual conversion (Brancucci et al, 2018;Brancucci et al, 2017). Low plasma LysoPC levels were also associated with increased sexual conversion rates in human infections (Usui et al, 2019).…”

The molecular machinery of translational control in malaria parasites

“…) (e.g. Usui et al , ). Following a period of maturation, which lasts between 2 and 10 days and again is species‐dependent, mature gametocytes are able to transform into fertile gametes within less than 10 min, once taken up by a blood‐feeding mosquito.…”