Regulation of Sexual Commitment and Gametocytogenesis in Malaria Parasites

Abstract

Sexual differentiation of malaria parasites from the asexual blood stage into gametocytes is an essential part of the life cycle, as gametocytes are the form that is taken up by the mosquito host. Because of the essentiality of this process for transmission to the mosquito, gametocytogenesis is an extremely attractive target for therapeutic interventions. The subject of this review is the considerable progress that has been made in recent years in elucidating the molecular mechanisms governing this important differentiation process. In particular, a number of critical transcription factors and epigenetic regulators have emerged as crucial elements in the regulation of commitment. The identification of these factors has allowed us to understand better than ever before the events occurring prior to and during commitment to sexual development and offers potential for new therapeutic interventions.

Keywords: AP2-G; Plasmodium; gametocyte; gametocytogenesis; malaria; malaria pathogenesis; sexual development.

Figure 1

The life cycle of Plasmodium falciparum. (❶) Liver cells are invaded by sporozoites introduced to the human by the bite of an infected mosquito. (❷) Hepatic merozoites develop and are subsequently released into the blood, where they invade erythrocytes. Once in the erythrocyte, Plasmodium parasites replicate to produce new merozoites that will either (❸) continue asexual development or (❹) be committed to sexual differentiation into gametocytes during the next erythrocytic cycle. (❺) Late-stage gametocytes can be picked up in a blood meal by a mosquito. For transmission, both a male and a female must be taken up by a mosquito, activate, fertilize, and produce an oocyst, where tens of thousands of sporozoites are produced. Once released from the oocyst about 12 days later, the sporozoites migrate to the salivary gland, where they can be transmitted to another human during a blood meal. Inset ❷ adapted with permission from Reference .

Figure 2

Model for the regulation of commitment and gametocytogenesis. In the presence of lysophosphatidylcholine (LysoPC), the ap2-g locus is epigenetically silenced through the effects of HP1 and Hda2, and cells continue to develop asexually. In the presence of lower levels of LysoPC, parasites are more likely to commit to gametocytogenesis. This process involves the removal of HP1 from the ap2-g locus (likely by GDV1), and transcription of ap2-g (likely by AP2-G3). Downstream of AP2-G, other epigenetic and transcriptional regulators are expressed, thus continuing the gametocyte transcriptional program while AP2-G2 simultaneously represses asexual-, liver-, and mosquito-stage genes. RNA-binding proteins such as Puf1 and Puf2 are important in modulating transcript levels. Adapted with permission from Reference .