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Sexual development in Plasmodium parasites: knowing when it's time to commit

Key Points

  • Malaria is responsible for almost 600,000 deaths each year; a major challenge in eradicating this disease has been the lack of drugs targeting malaria parasites at a transmissible stage of the life cycle.

  • Conversion of asexual blood-stage malaria parasites to sexual gametocytes is essential for transmission from the human host to the mosquito vector. This process occurs in only a small proportion of cells.

  • Although several studies have investigated the transcriptional changes that occur during sexual development and attempted to identify genes that may be involved, the molecular basis of sexual conversion has been elusive.

  • Recent work has identified an apicomplexan-specific transcription factor as a key regulator of commitment to gametocyte development.

  • Epigenetic and post-transcriptional mechanisms are also crucial in regulating sexual development.

  • The molecular events that integrate the signals that trigger commitment remain unknown and deserve further investigation.

Abstract

Malaria is a devastating infectious disease that is caused by blood-borne apicomplexan parasites of the genus Plasmodium. These pathogens have a complex lifecycle, which includes development in the anopheline mosquito vector and in the liver and red blood cells of mammalian hosts, a process which takes days to weeks, depending on the Plasmodium species. Productive transmission between the mammalian host and the mosquito requires transitioning between asexual and sexual forms of the parasite. Blood- stage parasites replicate cyclically and are mostly asexual, although a small fraction of these convert into male and female sexual forms (gametocytes) in each reproductive cycle. Despite many years of investigation, the molecular processes that elicit sexual differentiation have remained largely unknown. In this Review, we highlight several important recent discoveries that have identified epigenetic factors and specific transcriptional regulators of gametocyte commitment and development, providing crucial insights into this obligate cellular differentiation process.

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Figure 1: The life cycle of Plasmodium falciparum.
Figure 2: The stages of gametocyte development in Plasmodium falciparum.
Figure 3: Proposed model for the regulation of sexual commitment in Plasmodium falciparum.

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Acknowledgements

The authors apologize to all whose work could not be cited owing to space limitations. The authors acknowledge funding from the US National Institutes of Health (grant R01 AI076276) and support from The Pennsylvania State University. G.A.J. is supported by the Sir Keith Murdoch Fellowship from the American Australian Association.

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Glossary

Trophozoite

A highly metabolically active asexual form of the malaria parasite that forms during the intra-erythrocytic developmental cycle following the ring stage.

Schizont

A multinucleated, asexual form of the malaria parasite that forms during the intra-erythrocytic developmental cycle after several rounds of replication. Mature schizonts contain many merozoites, which are released when the red blood cell ruptures.

Ring-stage parasite

An asexual form of the malaria parasite that forms very soon after invasion of the red blood cell by a merozoite during the intra-erythrocytic developmental cycle.

Merozoite

Cell released either from intra-erythrocytic schizonts or from infected hepatocytes that can invade red blood cells.

Schizogony

The process by which many merozoites are produced through asexual reproduction.

Xanthurenic acid

A metabolite found in the mosquito mid-gut that induces gametogenesis in Plasmodium spp..

Exflagellation

The process by which flagellated male gametes are produced and released from a male gametocyte (for Plasmodium spp., in the mosquito mid-gut).

Oocysts

Structures formed by ookinetes (for Plasmodium spp., in the mosquito mid-gut) from which sporozoites are released.

Sporozoites

Cells that are released from oocysts. Plasmodium spp. sporozoites reside in the salivary glands of the mosquito. These are released into the bloodstream of the human host on infection and then invade liver cells.

Haemocoel

The body cavity of the mosquito.

Glucose-6-phosphate dehydrogenase

An enzyme involved in the pentose phosphate pathway. In humans, genetic deficiency of this enzyme leads to an increased risk of haemolysis, particularly in response to certain triggers.

Extracellular vesicles

Small vesicles that are released by cells from all three domains of life; in malaria infections, extracellular vesicles are released by infected red blood cells and are thought to have a role in cell–cell communication.

Parasitophorous vacuole

A vacuole that surrounds an intracellular parasite (in the case of the malaria parasite, within the red blood cell).

Gametocytaemia

The fraction of red blood cells that contain gametocytes.

Limiting dilution cloning

A method used to obtain parasite lines derived from a single parasite. The parental cell line is heavily diluted and grown in individual wells so that on average no more than one parasite is present per well.

Subtelomeric genes

Genes located in close proximity to the telomere.

Differential display analysis

A PCR-based method for identifying differentially expressed genes between two samples.

Chromatin immunoprecipitation followed by sequencing

A genome-wide approach that uses next-generation sequencing to identify DNA sequences directly or indirectly bound by a protein (such as a transcription factor or modified histone).

Euchromatin

Loosely packaged chromatin that is transcriptionally permissive — this is the predominant state of the chromatin in Plasmodium falciparum.

Heterochromatin

Tightly packaged chromatin that is associated with silencing marks such as histone H3 trimethylated on lysine 9 (H3K9me3). Genes in these regions are generally silenced.

Chromatin

DNA packaged with proteins (particularly histones, but also other proteins).

RNA fluorescence in situ hybridization

A technique used to visualize the location of a specific mRNA in the cell by using nucleic acid probes complementary to the target that are coupled to a fluorescent molecule.

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Josling, G., Llinás, M. Sexual development in Plasmodium parasites: knowing when it's time to commit. Nat Rev Microbiol 13, 573–587 (2015). https://doi.org/10.1038/nrmicro3519

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