Gametocytes are sexual precursor cells of the malaria parasite that mediate the transmission of the parasite from its mammalian host to the Anopheles mosquito. Unlike the asexual blood stages, which are responsible for the clinical outcome of malaria, gametocytes cause no clinical manifestations. However, they are very crucial for the transmission of the disease thus represent key targets for transmission-blocking interventions. Despite their essential role in malaria transmission, only in the last decade gametocytes became a hot topic of research and their biology is not well understood. This chapter provides a detailed review on the biology of the human malaria gametocytes with emphasis on aspects such as gametocyte commitment, gametocyte maturation (gametocytogenesis), gametocyte metabolism and gametogenesis. Proper understanding of these processes will deepen our knowledge on the gametocyte biology and therefore open up more avenues for the development of malaria transmission-blocking intervention strategies.
- sexual reproduction
Gametocytes are specialized sexual precursor cells that mediate the transmission of the malaria parasite from the mammalian host to the mosquito. Once these cells have gained maturity, they are picked up by an
Despite their essential role in maintaining the parasite life cycle, research on gametocytes has been very much left out of the limelight. Several reasons could be accounted for this: first, gametocytes cause no clinical manifestation in their host as opposed to the asexual blood stages that are responsible for the clinical features of malaria. Second, it has been a great challenge to culture gametocytes because of the cost and time-consuming cultivation procedure, and finally, it has been a hurdle to obtain pure gametocytes for molecular and metabolic studies as well as drug screening purposes. However, in the last decade, the rapid emergence of drug-resistant parasites and mosquitoes, together with the absence of a malaria vaccine, has rekindled the interest of researchers on alternative measures aimed at interrupting the parasite life cycle by targeting gametocytes. This interest has led to the improvement of gametocyte cultivation and purification methods, which have enabled a greater understanding of the gametocyte biology.
In this chapter, we focus on key aspects of the gametocyte biology such as gametocyte commitment, maturation (gametocytogenesis), metabolism and gametogenesis. This will deepen our understanding on the biology of gametocytes and thereby open up more avenues for the development of malaria transmission-blocking intervention strategies.
2. Gametocyte commitment
The asexual blood stage parasites produce the clinical form of malaria due to destruction of the erythrocytes, while replicating in the mammalian host. However, these asexual blood stages cannot be transmitted to the mosquito to continue the life cycle of the parasite. For this reason, a subset of the asexual blood stages is able to switch to the sexual pathway, resulting in the formation of the sexual precursor cells, the gametocytes. The process of switching from the asexual blood stage to the gametocyte is referred to as gametocyte commitment.
Commitment to gametocyte development is believed to take place at some point before schizogony, in which each individual schizont produces a progeny of merozoites that develop into either sexual forms or asexual blood stage parasites, which continue the erythrocytic cycle [2, 3] (Figure 1). In addition, merozoites released from a single sexually committed schizont can either become male or female gametocytes and the characteristic female-biased sex ratio observed in the malaria parasite is due to the production of a higher percentage of committed female schizonts than their male counterpart [3, 4].
Until recently, gametocyte commitment was mainly assigned to stress factors such as high parasitaemia, anaemia, host immune response or drug treatment, with an overwhelming amount of studies to justify these facts. A study by Chaubey and colleagues suggested that the malaria parasite reacts to endoplasmic reticulum stress by switching to gametocytes . The treatment of mice with phenylhydrazine, which induces hyper-reticulocyte formation, stimulates gametocyte formation when infected with
However, despite the knowledge that gametocyte commitment can be enhanced by stress factors, the mechanism by which stress induces this process is not well understood. Recent studies have also associated gametocyte commitment to the concerted action of epigenetics and transcriptional regulation.
2.1. Epigenetic mechanism of gametocyte commitment
Epigenetic mechanisms through histone modifications have been shown to regulate gene expression of important proteins in the malaria parasite [13, 14]. In
Heterochromatin protein 1 (HP1) was initially described in
Histone deacetylases are histone-modifying enzymes that promote transcriptional silencing by removing acetyl groups from histones. The removal of the acetyl groups facilitates histone methylation and HP1 binding [18, 21, 22], thereby resulting in reduced accessibility for transcriptional factors and heterochromatin formation. A study by Coleman and colleagues , which complements the results of Brancucci et al. , showed an essential role of PfHda2 in the global silencing of
2.2. Transcriptional regulation of gametocyte commitment
AP2-G is a member of the apicomplexan AP2 DNA-binding protein family, characterized by the presence of an Apetala2/ethylene response factor (AP2/ERF) DNA-binding domain . In the malaria parasite, other AP2 proteins have been assigned to the stage-specific transition during parasite development, for example, the development of midgut, sporozoite and liver stages [24–27].
Two studies in
During the malaria life cycle, therefore, two populations of the malaria parasite exist. Non-committed parasites, which continue the erythrocytic cycle, and committed parasites that form gametocytes. In the case of non-committed parasites, PHP1 binds to H3K9me3 residues thereby maintaining the
3. Gametocyte maturation
3.1. Gametocyte morphology
The morphology of gametocytes varies among the
Among the other species of malaria,
One remarkable morphological feature of gametocytes is the presence of the inner membrane complex (IMC), which underlies the plasmalemma and consists of flat membranous sacs called alveoli that are coupled to a supporting cytoskeletal network. The IMC was originally assigned to the invasive stages of
3.2. Gametocyte-specific proteins
Approximately 20% of all plasmodial genes are specifically expressed in the sexual stages [45, 46]. In
In the early stage I–II gametocytes, important proteins such as Pfs16, Pfg27 and the six LCCL-domain proteins are expressed . Pfs16 is present in all gametocyte stages, but it is initially expressed in stage I. It is localized in the parasitophorous vacuole (PV) where it plays a role in gametocyte development [51–53]. The main function of Pfs16 is unknown, but its disruption leads to a decrease in gametocyte production and an impairment in the ability of microgametocyte to exflagellate . The protein Pfg27 is a phosphoprotein that starts to be expressed from stage II. It is known that Pfg27 forms a homodimer to act as single-stranded RNA-binding proteins
Starting from stage IIb, well-known sexual-stage proteins such as the 6-cys proteins Pfs48/45 and Pfs230 and the osmiophilic body protein Pfg377 and Pfmdv-1 or sexual stage-specific cytoskeletal proteins such as α-tubII (tubulin II) and actin II are synthesized . Similar to the six LCCL-domain proteins, the surface proteins Pfs48/45 and Pfs230 have adhesive properties and gene disruption of both proteins impair male gamete fertility [59, 60]. Pfg377 is known to be associated with osmiophilic bodies in female gametocyte of
In the gametocytes of
4. The gametocyte metabolism
As vital molecules, lipids are responsible for many functions such as cell signalling, energy storage and the stability of membranes. Furthermore, during the various stages of the
In gametocytes, no DNA-replication occurs  and the nucleic acid synthesis is exclusive for RNA production. The production of RNA ceases from around day 6 of gametocytogenesis, thus the RNA and protein synthesis are more important in the early than late gametocyte stages [77, 78]. One interesting feature of malaria parasites is the expression of small subunit ribosomal RNA (SSU rRNA) genes , seven of them are synthesized in
In eukaryotes, the mitochondria have many vital roles such as ATP synthesis, calcium homeostasis, lipid metabolism and synthesis of ion-sulphate clusters. The malaria parasites only possess a single mitochondrion and during parasite development it is observed that the mitochondria of gametocytes are longer and possess more cristae when compare to the ones of the asexual blood stages. This suggests that ATP synthesis via the electron transport chain is the main mechanism of energy production in gametocytes [29, 33]. Indeed the sexual stages appear to have seven times more cytochrome b than the asexual blood stages . The cytochrome bc1 complex feeds the electron transport chain with more protons, which creates a gradient that drives ATP synthesis . The cytochrome bc1 is a prime target for the antimalarial drug atovaquone that inhibits ubiquinone leading to the inhibition of
Despite the fact that the mitochondria have been well characterized in other organisms, many mitochondrion-associated events in
5. Gametocyte activation and gametogenesis
5.1. The signalling cascade of gametocyte activation
The mature stage V gametocytes, which circulate in the blood of the mammalian host, are picked up by the female
While the plasmodial receptor or receptors important for signal perception are still unknown, the signalling pathway resulting in gametogenesis has partially been deciphered (Figure 3). It has previously been shown that male gametogenesis, during which the activated male microgametocyte forms eight motile flagellar microgametes (a process termed exflagellation), involves a fast increase in intracellular calcium and the second messenger cGMP [92, 93]. Two membrane-integrated guanylyl cyclases (GCα and GCβ) were identified in
While in eukaryotes, cGMP is synthesized by guanylyl cyclases, phosphodiesterases (PDEs), which hydrolyse cGMP to GMP, are in general required for fast down-regulation of the second messenger. In
The increase in cGMP activates the cGMP-dependent protein kinase PKG and chemical inhibition of PKG impairs rounding-up of the activated gametocytes. Since rounding-up is a calcium-independent step and cannot be inhibited by calcium chelators (see below), PKG acts prior to calcium increase in the activated gametocytes . Gametocyte activation further leads to the generation of the second messenger molecules DAG and inositol-(1,4,5)-trisphosphate (IP3) from phosphatidylinositol-(4,5)-bisphosphate (PIP2) via the plasmodial phospholipase PI-PLC activity (Figure 3), as shown in
In female macrogametocytes, activation results in a sudden onset of protein synthesis, which is due to the CDPK1-regulated release of translational repression of messenger RNAs (mRNAs) . In
5.2. Gametocyte egress and gamete formation
Gametocyte activation results in three morphological changes in the parasites, i.e. rounding-up, erythrocyte egress and gamete formation, and these changes occur with approximately 15 min following perception of the environmental signals (Figure 4). Gametocytes exit the erythrocyte via an inside-out mode, during which the parasitophorous vacuolar membrane (PVM) ruptures prior to the opening of the erythrocyte membrane (EM). Rupture of the PVM occurs at multiple sites less than 2 min following signal perception and is accompanied by the rounding-up of the parasite. Both events are calcium-independent [91, 99]. It is suggested that the PVM rupture is linked to the discharge of the osmiophilic body content into the PV, since an accumulation of osmiophilic bodies can be observed underneath the rupture sites [91, 115].
In a second, a calcium-dependent step, another type of vesicle discharges its content into the cytoplasm of the host erythrocyte, which includes the plasmodial pore-forming perforin PPLP2. This perforin is able to permeate the EM, resulting in the release the erythrocyte cytoplasm, eventually leaving the forming gamete enclosed by the EM [115–117]. While EM permeabilization occurs approximately 6 min post-activation, its rupture takes place 9 min later. Here, the EM opens at a single pore and releases the fertile gamete [91, 117].
The IMC disintegrates shortly after onset of gametogenesis, eventually resulting in gametes solely confined by the plasmalemma. It was shown that the transmembrane protein GAP50, which in gametocytes, is located in the outer membrane of the alveoli, relocates to the gamete plasmalemma during gametogenesis. During relocation, the N-terminal part of GAP50 becomes extracellularly exposed and once the gametes have freed from the EM binds complement factor H from the blood meal, a step crucial to protect the newly formed gametes from lysis by human complement factors . Coevally with the IMC degradation long membranous tubules, termed tunneling nanotubes (TNTs), form, which protrude from the gamete surface. TNTs represent long-distance cell-to-cell connections, which were proposed to mediate intercellular contacts between gametes as a pre-requisite for mating . While the question of the origin of the membranous tubules remains unanswered, one might stipulate that after IMC disintegration the alveoli membranes are used for TNT formation.
Upon activation, the male microgametocyte replicates its genome three times and mitotically produces eight flagellar microgametes  (Figure 4). Flagellum formation requires the axonemal assembly from basal bodies, which involves the centriole/basal body protein SAS-6 , while axoneme motility is regulated by the conserved armadillo-repeat protein PF16 . Exflagellating microgametes typically adhere avidly to neighbouring erythrocytes and are hidden within such rosettes. During exflagellation, the microgamete detaches from the residual body and is freely motile in search of a female macrogamete. Once adhering to a macrogamete, fertilization begins by the fusion of the two gamete plasma membranes, and the axoneme and attached male nucleus enter the female cytoplasm. While the exact proteins involved in initial binding of male and female gametes are yet unknown, gamete fusion is mediated by the microgamete-specific protein GCS1 (generative cell specific 1), also termed HAP2 [122, 123]. Over the next 3 hours, meiosis occurs and the zygote becomes tetraploid . The transformation of the zygote into an ookinete is completed at 19–36 hours post-blood meal, and the ookinete then rapidly exits the midgut lumen to settle down at the basal site of the midgut epithelium and to differentiate into an oocyst [124–127]. Parasite tetraploidy persists until sporozoite budding in the oocyst restores the haploid state .
Although our knowledge of the biology of gametocytes is not as advanced as that of the asexual blood stages, the great interest by researchers in recent years has considerably deepened our understanding of the gametocyte biology. Advances in gametocyte cultivation, isolation and purification techniques as well as the impressive amount of data gained from genome-wide analyses, proteomics and microarray studies have led to the identification of some gametocyte stage-specific antigens as well as sex-specific proteins, which may be exploited as targets for malaria transmission-blocking intervention strategies. In addition, the recent discoveries on the molecular mechanism of gametocyte commitment have greatly improved our knowledge on how sexual differentiation is initiated and regulated in the malaria parasite. However, several questions are still to be answered regarding the biology of gametocytes. The mechanism by which stress factors are perceived to enhance gametocyte commitment is not well understood. Some components of the signalling cascade of gametocyte activation are yet unknown such as the receptor or receptors responsible for signal perception following gametocyte activation by XA. How gametocyte sequestration in the bone marrow takes place as well as the molecular mechanism underlying this phenomenon has to been deciphered. Also, a proper understanding of the mechanism by which the gametocyte rapidly adapts once in the mosquito vector and the basis of fertilization is needed. Furthermore, not much is known about the metabolism of gametocytes. Most of the metabolic pathways have not been described. A proper understanding of these aspects in the biology of gametocytes would greatly improve strategies aimed to target gametocytes.
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