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![Morphological features of gametocytes across Plasmodium lineages. Shown are representative electron microscopy images and drawings of gametocytes of (A) human (P. falciparum), (B) rodent (P. berghei) and (C) avian (P. gallinaceum) malaria parasites. Mitochondria (M), apicoplast (A), nucleus (N), endoplasmatic reticulum (ER) and the food vacuole (FV) containing hemozoin crystals (marked with an asterisk) are found in all Plasmodium species in both male and female gametocytes. The gametocyte plasma membrane (PM) is in close association with the parasitophorous vacuolar membrane (PVM), and in most cases with the IMC (depicted in the closeup insets of the electron micrographs). Whilst the nucleus is smaller and more compact in female compared to male gametocytes, the ER is more developed in female gametocytes, in line with increased translation. Osmiophilic bodies (OB, marked with an arrow) are found in all species, with a higher number in female than in male gametocytes. (A) Ultrastructure of immature stage III and mature stage V P. falciparum gametocytes. Upper panel: Electron micrograph (left) and drawing (middle: longitudinal section, right: cross-section) of a stage III gametocyte. The IMC develops along one side of the gametocyte, supported by underlying microtubules (Mt)(depicted in the inset). Some microtubules are also found on the opposing side (see cross-section). Additionally, actin filaments (Act) are found, in particular at the tips of the developing gametocyte. MC are found within the erythrocyte cytoplasm. Lower panel: Electron microscope image and drawing of a female (left) and male (right) stage V gametocyte. The IMC plates now completely surround the gametocytes whilst actin and microtubules are absent. In the female gametocyte osmiophilic bodies are located along the periphery of the cell. In contrast they have not been described in male P. falciparum gametocytes. (B) Electron micrograph and drawing of mature female (left) and male (right) P. berghei gametocytes. Osmiophilic bodies are oval (oOB) and more abundant in female gametocytes, whilst male gametocytes have fewer and club-shaped osmiophilic bodies (cOB). The IMC is difficult to observe in female gametocytes and possibly absent, whilst a discontinuous IMC (dIMC) is clearly detectable in male P. berghei gametocytes (see insets) (Mons 1986). (C) Electron micrograph and scheme of mature female (left) and male (right) P. gallinaceum gametocytes. Electron micrographs are taken from (Aikawa et al. 1969)(female) and (Sterling and Aikawa 1973)(male) [PERMISSION PENDING]. In contrast to mammalian mature RBCs, avian mature RBCs are nucleated (depicted as host nucleus (HN)).](publication/333930874/figure/fig2/AS:779168488882182@1562779652937/Morphological-features-of-gametocytes-across-Plasmodium-lineages-Shown-are.jpg)
Morphological features of gametocytes across Plasmodium lineages. Shown are representative electron microscopy images and drawings of gametocytes of (A) human (P. falciparum), (B) rodent (P. berghei) and (C) avian (P. gallinaceum) malaria parasites. Mitochondria (M), apicoplast (A), nucleus (N), endoplasmatic reticulum (ER) and the food vacuole (FV) containing hemozoin crystals (marked with an asterisk) are found in all Plasmodium species in both male and female gametocytes. The gametocyte plasma membrane (PM) is in close association with the parasitophorous vacuolar membrane (PVM), and in most cases with the IMC (depicted in the closeup insets of the electron micrographs). Whilst the nucleus is smaller and more compact in female compared to male gametocytes, the ER is more developed in female gametocytes, in line with increased translation. Osmiophilic bodies (OB, marked with an arrow) are found in all species, with a higher number in female than in male gametocytes. (A) Ultrastructure of immature stage III and mature stage V P. falciparum gametocytes. Upper panel: Electron micrograph (left) and drawing (middle: longitudinal section, right: cross-section) of a stage III gametocyte. The IMC develops along one side of the gametocyte, supported by underlying microtubules (Mt)(depicted in the inset). Some microtubules are also found on the opposing side (see cross-section). Additionally, actin filaments (Act) are found, in particular at the tips of the developing gametocyte. MC are found within the erythrocyte cytoplasm. Lower panel: Electron microscope image and drawing of a female (left) and male (right) stage V gametocyte. The IMC plates now completely surround the gametocytes whilst actin and microtubules are absent. In the female gametocyte osmiophilic bodies are located along the periphery of the cell. In contrast they have not been described in male P. falciparum gametocytes. (B) Electron micrograph and drawing of mature female (left) and male (right) P. berghei gametocytes. Osmiophilic bodies are oval (oOB) and more abundant in female gametocytes, whilst male gametocytes have fewer and club-shaped osmiophilic bodies (cOB). The IMC is difficult to observe in female gametocytes and possibly absent, whilst a discontinuous IMC (dIMC) is clearly detectable in male P. berghei gametocytes (see insets) (Mons 1986). (C) Electron micrograph and scheme of mature female (left) and male (right) P. gallinaceum gametocytes. Electron micrographs are taken from (Aikawa et al. 1969)(female) and (Sterling and Aikawa 1973)(male) [PERMISSION PENDING]. In contrast to mammalian mature RBCs, avian mature RBCs are nucleated (depicted as host nucleus (HN)).
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Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria trans...
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... parts of the Plasmodium transmission cycle are conserved across the genus (Fig. 2); however, there are notable differences in cycle length and morphology between lineages. The conserved features enable utilization of animal models for in vivo studies of transmission biology. The first developmental stage that is functionally different from an asexual parasite is the sexually committed schizont. Commitment to ...
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... begins to differ from the one of asexual parasites. In stage II, slight changes in appearance become apparent, as the parasite takes the shape of a lemon or oat grain with one pointed end. The parasite then elongates whilst one side flattens and the opposite membrane curves, so that in stage III the shape of the parasite resembles the letter 'D' (Fig. 2A). The length of the parasite exceeds the diameter of the RBC, which exhibits signs of deformation. Developing into stage IV, the parasite elongates even more, now resembling the shape of a banana. The RBC cytoplasm is almost completely occupied with the parasite, except for a small membrane fold known as the Laveran's bib. Stage V ...
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... parasite elongates even more, now resembling the shape of a banana. The RBC cytoplasm is almost completely occupied with the parasite, except for a small membrane fold known as the Laveran's bib. Stage V gametocytes exhibit the characteristic crescent shape with rounded ends, as opposed to the pointed ends of stage IV gametocytes (Sinden 1982) (Fig. 2A). Apart from the likely conservation in Laverania, the morphological features of P. falciparum gametocytes are not conserved across the Plasmodium lineage: most gametocytes from rodent, bird and primate parasites are round and resemble the trophozoite stage (Sinden et al. 1978;Walzer et al. 2018) (Fig. 2B and C). The 9-12 day maturation ...
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... of stage IV gametocytes (Sinden 1982) (Fig. 2A). Apart from the likely conservation in Laverania, the morphological features of P. falciparum gametocytes are not conserved across the Plasmodium lineage: most gametocytes from rodent, bird and primate parasites are round and resemble the trophozoite stage (Sinden et al. 1978;Walzer et al. 2018) (Fig. 2B and C). The 9-12 day maturation time for P. falciparum gametocytes is exceptionally long, whereas the development in other primate, avian and rodent Plasmodium species ranges from 24 to 60 hours ( Gautret and Motard 1999). In addition following development, and in contrast to species with shorter developmental periods that survive for less ...
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... same time IMC membranes spread over the cell body, finally engulfing it. In P. falciparum gametocytes IMC assembly is initiated by unknown factors and starts in stage I/II gametocytes with the deposition of a single patch of vacuolar membrane and microtubules underneath the parasite membrane (Sinden 1982;Dearnley et al. 2012;Dearnley et al. 2016) (Fig. 2A). Additional membrane sacs, originated from the endoplasmic reticulum (ER), are deposited at the periphery along one side of the developing gametocyte in a string of beads pattern. This side will form the 'foot', the flattened membrane of the stage III gametocyte. Even though gametocytes, as opposed to the motile stages of P. ...
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... of most Plasmodium species, including avian and reptilian malaria parasites, possess an IMC (Aikawa, Huff and Sprinz 1969). However, some species, e.g. P. berghei (Olivieri et al. 2015) and P. knowlesi (Aikawa, Huff and Sprinz 1969) exhibit discontinuities within the IMC, i.e. the IMC does not completely engulf the gametocyte (see also Fig. 2B). Interestingly, in P. berghei the discontinuous IMC is easily detected in male gametocytes, whilst in female gametocytes it may be absent (Mons 1986). As the main function of the IMC in gametocytes seems to be forming and stabilising the shape of the cell, Plasmodium species with round gametocytes might have less requirement for a ...
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... It was shown that actin forms filaments that are present underneath the microtubules and can be closely associated with them. These filaments appear very stable as they cannot be depolymerised using the actin polymerisation inhibitor Cytochalasin D. Throughout gametocyte development, actin accumulated at the opposing ends of the cell ( Fig. 2A) and co-localised with the actin nucleation factor formin-1, indicating that these are the sites of actin polymerisation. In contrast to the actin filaments associated with microtubules, these filaments are sensitive to treatment with Cytochalasin D. The function of the actin network in gametocytes is not fully understood, but it ...
Citations
... When a mosquito bites a primate, it injects sporozoites into the bloodstream, initiating the hepatic stage. After further development and schizogony, releasing merozoites invade erythrocytes, beginning the erythrocytic phase [3][4][5]. ...
Plasmodium knowlesi, a malaria parasite found in southeast Asia, can infect both primates and humans, potentially causing severe malaria. It is closely related to Plasmodium vivax, and its treatment utilizes chloroquine or artemisinin combination therapy. Plasmodium knowlesi presents significant health and economic challenges due to its zoonotic nature. However, it also serves as a valuable model for scientific research, aiding in vaccine development and understanding malaria invasion mechanisms. Its use facilitates progress in pharmaceutical investigations and the establishment of in vitro culture methods with both primate and human cells.
... On the other hand, P. falciparum circumsporozoite protein (PfCSP) is the most abundant protein of the pre-erythrocytic infective stage of the parasite, and is critical for sporozoite function and development in infected mosquitoes, invasion of mosquito salivary glands, as well as adhesion and invasion of hepatocytes required for initiation of the infection (Ancsin & Kisilevsky, 2004;Coppi et al., 2007Coppi et al., , 2011Livingstone et al., 2021). Lastly, the glycoprotein P. falciparum merozoite surface protein 1 (PfMSP1) abounds greatly on the surface of erythrocyte-invading Plasmodium merozoite and is crucially important in the invasion of the human RBC (Cowman & Crabb, 2006;Gilson et al., 2006;Lin et al., 2014), the stage that is connected with the clinical manifestations and complications of malaria (Ngotho et al., 2019). Due to the unique roles played by these proteins in P. falciparum immunogenicity, virulence, survival and transmission, as well as clinical severity and pathogenesis of malaria, targeting these protein receptors may contribute to the attenuation of the disease (Bull & Abdi, 2016;Lin et al., 2016;Turner et al., 2013). ...
The emergence of varying levels of resistance to currently available antimalarial drugs significantly threatens global health. This factor heightens the urgency to explore bioactive compounds from natural products with a view to discovering and developing newer antimalarial drugs with novel mode of actions. Therefore, we evaluated the inhibitory effects of sixteen phytocompounds from Cymbopogon citratus leaf extract against Plasmodium falciparum drug targets such as P. falciparum circumsporozoite protein (PfCSP), P. falciparum merozoite surface protein 1 (PfMSP1) and P. falciparum erythrocyte membrane protein 1 (PfEMP1). In silico approaches including molecular docking, pharmacophore modeling and 3D-QSAR were adopted to analyze the inhibitory activity of the compounds under consideration. The molecular docking results indicated that a compound swertiajaponin from C. citratus exhibited a higher binding affinity (−7.8 kcal/mol) to PfMSP1 as against the standard artesunate-amodiaquine (−6.6 kcal/mol). Swertiajaponin also formed strong hydrogen bond interactions with LYS29, CYS30, TYR34, ASN52, GLY55 and CYS28 amino acid residues. In addition, quercetin another compound from C. citratus exhibited significant binding energies −6.8 and −8.3 kcal/mol with PfCSP and PfEMP1, respectively but slightly lower than the standard artemether-lumefantrine with binding energies of −7.4 kcal/mol against PfCSP and −8.7 kcal/mol against PfEMP1. Overall, the present study provides evidence that swertiajaponin and other phytomolecules from C. citratus have modulatory properties toward P. falciparum drug targets and thus may warrant further exploration in early drug discovery efforts against malaria. Furthermore, these findings lend credence to the folkloric use of C. citratus for malaria treatment.
Communicated by Ramaswamy H. Sarma
... Approximately 5-7 days after the stage I gametocyte is formed, it undergoes a maturation process that results in a mature stage V female or male gametocyte [47]. The creation of a pellicular complex beneath the gametocyte plasma membrane in late stage I, which gives the gametocyte its crescent shape, is a significant morphological feature of developing gametocytes [48]. ...
... Stage IV's enhanced deformability may be due to stage V STEVOR internalization, which takes place, while it is still attached to the RBC membrane in stage IV. It may be necessary to make adjustments to the host cytoskeleton network, including spectrin and band 3, similar to the reported deformability switch during gametocyte development [48]. ...
Understanding the cellular and molecular biology of any infectious agent is the mainstay of its successful prevention and control. Therefore, in this review, various aspects of the cellular and molecular biology of the Plasmodium parasite were critically reviewed. Plasmodium parasite is characterized by the presence of three different invasive forms (Sporozoites, Merozoites, and Ookine/Oocyte), which are morphologically and genetically distinct. The size of the Plasmodium genome, which comprises nuclear, plastid, and mitochondrial genomes ranges in size from 20 to 35 megabase (Mb) with 23 million bases, which translate into 7132 genes in Plasmodium ovale and 5507 in Plasmodium falciparum. Plasmodium species are found to be the most AT-rich genome (80%), and their GC% contents are merely less than 20%. Gametocytogenesis indicates the commencement of the sexual development, which is regulated by signal transduction and expression of genes such as Pfs16, Pf14.744, Pf14.748, Pfpeg3/mdv1, and Pfpeg4. In these stages, only 20% of all Plasmodial genes are expressed.
... [31,32] This commitment is initiated by the activation of the transcription factor AP2-G (a DNA-binding protein of the ApiAP2 family) in rodent parasites and P. falciparum. [33][34][35] Gametocyte development is categorized in five stages (I-V)_which are accompanied by a tightly regulated expression of sexual stage genes which peak at distinct times: (stage III). [36] For proper maturation purposes the gametocytes retract from the peripheral blood and sequester for approximately 8-12 days within organs, the bone marrow and the spleen cords where they remain hidden until they have reached stage V of their development. ...
... [60] These tethers can only be found in the subgenus Laverania, which suggests that their occurrence is specific for this lineage. [33] Spectrin, a heterodimeric protein which is an integral part of the RBC membrane skeleton and responsible for the elasticity of the RBC, is apparently not MC-associated within RBC infected with asexually replicating parasites. [60,69] Vesicular structures with different sizes (25 and 80 nm) and different electron densities that surround the mature MC have been described by different laboratories. ...
... Proteins with one or more transmembrane domains can be found at the organelle before their journey to the final destination on the RBC surface continues. [33,67,122] One of the most important protein families that needs to be processed by the organelle is the PfEMP1 family. (Table 2). ...
Reorganization of cell organelle-deprived host red blood cells by the apicomplexan malaria parasite Plasmodium falciparum enables their cytoadherence to endothelial cells that line the microvasculature. This increases the time red blood cells infected with mature developmental stages remain within selected organs such as the brain to avoid the spleen passage, which can lead to severe complications and cumulate in patient death. The Maurer's clefts are a novel secretory organelle of parasite origin established by the parasite in the cytoplasm of the host red blood cell in order to facilitate the establishment of cytoadherence by conducting the trafficking of immunovariant adhesins to the host cell surface. Another important function of the organelle is the sorting of other proteins the parasite traffics into its host cell. Although the organelle is of high importance for the pathology of malaria, additional putative functions, structure, and genesis remain shrouded in mystery more than a century after its discovery. In this review, we highlight our current knowledge about the Maurer's clefts and other novel secretory organelles established within the host cell cytoplasm by human-pathogenic malaria parasites and other parasites that reside within human red blood cells.
... At the same time, species-specific biological differences may complicate the extrapolation of findings to other species. For example, between species clear differences exist in gametocyte biology, not only at the level of morphology, maturation rate and longevity, but also in the genes involved in gametocyte development [36]. To date, successful transmission of P. cynomolgi has only been described following a monkey passage. ...
Plasmodium vivax causes the second highest number of malaria morbidity and mortality cases in humans. Several biological traits of this parasite species, including the formation of dormant stages (hypnozoites) that persist inside the liver for prolonged periods of time, present an obstacle for intervention measures and create a barrier for the elimination of malaria. Research into the biology of hypnozoites requires efficient systems for parasite transmission, liver stage cultivation and genetic modification. However, P. vivax research is hampered by the lack of an in vitro blood stage culture system, rendering it reliant on in vivo derived, mainly patient material, for transmission and liver stage culture. This has also resulted in a limited capability for genetic modification, creating a bottleneck in investigations into the mechanisms underlying the persistence of the parasite inside the liver. This bottleneck can be overcome through optimal use of the closely related and experimentally more amenable nonhuman primate (NHP) parasite Plasmodium cynomolgi as model system. In this review we discuss the genetic modification tools and liver stage cultivation platforms available for studying P. vivax persistent stages and highlight how their combined use may advance our understanding of hypnozoite biology.
... We did not perform further experiments because previous studies testing the PfFNT inhibitors during sexual development showed only a very modest reduction during stage-I parasite development, but not in later stages (24). Data on the energy metabolism of gametocytes are still scarce (25); it was found that the main glycolytic product of gametocytes is acetate-CoA, which may feed into a functional aerobic tricarboxylic acid (TCA) cycle (26,27). Furthermore, lipid consumption is increased in gametocytes, equally leading to acetate-CoA (28). ...
Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H+ from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its in vivo druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 × IC50 (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their in vivo activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials.
... Gametocytogenesis is initiated during the erythrocytic phase in the human host. The maturation of Plasmodium falciparum gametocytes takes about 10-12 days and occurs in the deep organs, notably in the bone marrow [10]. Mature gametocytes circulate in the peripheral circulatory system and are taken up by female Anopheles mosquitoes during subsequent blood meals. ...
... 9 Long-term cultivation failed, partly due to agglutination. 10 Poor during the adaptation period of primary isolate (first 57 days of cultivation); fair to good thereafter (culture terminated on day 74 of this study) [181]. ...
Successfully developed in 1976, the continuous in vitro culture of Plasmodium falciparum has many applications in the field of malaria research. It has become an important experimental model that directly uses a human pathogen responsible for a high prevalence of morbidity and mortality in many parts of the world and is a major source of biological material for immunological, biochemical, molecular, and pharmacological studies. Until present, the basic techniques described by Trager and Jensen and Haynes et al. remain unchanged in many malaria research laboratories. Nonetheless, different factors, including culture media, buffers, serum substitutes and supplements, sources of erythrocytes, and conditions of incubation (especially oxygen concentration), have been modified by different investigators to adapt the original technique in their laboratories or enhance the in vitro growth of the parasites. The possible effects and benefits of these modifications for the continuous cultivation of asexual intraerythrocytic stages of P. falciparum, as well as future challenges in developing a serum-free cultivation system and axenic cultures, are discussed.
... For the transmission from vertebrates to mosquitoes, the parasites go through sexual development (4,5). Sexual development begins with a subpopulation of the asexual blood-stage parasites differentiating into male and female gametocytes (6)(7)(8). After the gametocytes are ingested by mosquitoes through blood feeding, they egress from red blood cells to form microgamete and macrogamete in the mosquito midgut (9). ...
Gametocyte development of the Plasmodium parasite is a key step for transmission of the parasite from their vertebrate hosts to mosquitoes. Male and female gametocytes are produced from a subpopulation of asexual blood-stage parasites, but the mechanisms that regulate the differentiation of sexual stages are still under investigation. In this study, we investigated the role of gARID, a putative subunit of a chromatin remodeling complex, in transcriptional regulation during the gametocyte development of P. berghei. gARID expression starts in early gametocytes before the manifestation of male and female-specific features, and disruption of its gene results in the complete loss of male gametocytes and the production of abnormal female gametocytes. ChIP-seq analysis of gARID showed that it forms a complex with gSNF2, a core subunit of the SWI/SNF chromatin remodeling complex, associating with the male cis-regulatory element. Moreover, ChIP-seq of gARID in gsnf2-knockout parasites revealed an association of gARID with another cis-regulatory element, which is indicated to play a role in both male and female development. Our results showed that gARID functions in two chromatin remodeling events and that remodeling of chromatin states is essential for both male and female gametocyte development.
... The hypoproducer phenotypic group was enriched for gene ontology (GO) terms like RNA and protein binding, membrane, intracellular protein complex, and, interestingly, vesicle-mediated transport ( Fig. 1C; Data Set S2). While the importance of protein-RNA interactions in gametocyte regulation has been known for some time, the critical nature of the gametocyte inner membrane complex emerged only recently (45)(46)(47). The piggyBac mutants assigned to either of the gametocyte phenotype categories generally represented disruptions in genes that had increased expression in sexual stages compared to asexual (40). ...
... The highly conserved ER membrane complex (EMC) functions as an insertase in the ER membrane and facilitates membrane protein folding and assembly (68,69). Extensive membrane development is one of the hallmarks of gametocytogenesis in P. falciparum, and the EMC has been shown to be involved in phospholipid synthesis in malaria parasites (46,52,70,71). The inability to complete gametocyte maturation in the piggyBac mutant EMC3 and the absence of well-defined membrane structures emphasize a role of this gene in sexual development; nevertheless, additional studies are needed to validate gene function. ...
... This high conservation of gametocyte-critical genes across Plasmodium species may allow extension of our analyses to other important malaria parasites, such as Plasmodium vivax, which lacks an in vitro culture system, and may further allow insight into the transmission biology of emerging reverse-zoonotic human malaria pathogens, such as Plasmodium knowlesi. While most gametocyte-critical genes were conserved, we observed 9 genes that had no orthologs and were specific to P. falciparum ( Fig. S3B; Data Set S3), emphasizing the unique nature of P. falciparum gametocytogenesis (46). ...
Transmission of the deadly malaria parasite Plasmodium falciparum from humans to mosquitoes is achieved by specialized intraerythrocytic sexual forms called gametocytes. Though the crucial regulatory mechanisms leading to gametocyte commitment have recently come to light, networks of genes that control sexual development remain to be elucidated. Here, we report a pooled-mutant screen to identify genes associated with gametocyte development in P. falciparum. Our results categorized genes that modulate gametocyte progression as hypoproducers or hyperproducers of gametocytes, and the in-depth analysis of individual clones confirmed phenotypes in sexual commitment rates and putative functions in gametocyte development. We present a new set of genes that have not been implicated in gametocytogenesis before and demonstrate the potential of forward genetic screens in isolating genes impacting parasite sexual biology, an exciting step toward the discovery of new antimalarials for a globally significant pathogen. IMPORTANCE Blocking human-to-vector transmission is an essential step toward malaria elimination. Gametocytes are solely responsible for achieving this transmission and represent an opportunity for therapeutic intervention. While these falciform-shaped parasite stages were first discovered in the 1880s, our understanding of the genetic determinants responsible for their formation and molecular mechanisms that drive their development is limited. In this work, we developed a scalable screening methodology with piggyBac mutants to identify genes that influence the development of gametocytes in the most lethal human malaria parasite, P. falciparum. By doing so, we lay the foundation for large-scale functional genomic studies specifically designed to address remaining questions about sexual commitment, maturation, and mosquito infection in P. falciparum. Such functional genetic screens will serve to expedite the identification of essential pathways and processes for the development of novel transmission-blocking agents.
... P. falciparum has a complex life cycle [4,5]. It infects both human and mosquito hosts and undergoes numerous cellular transformations leading to distinct morphological and physiological changes in response to these altered environmental conditions (Figure 1). ...
... As an alternative to continuing the IDC by reinvading RBCs, a parasite subset can develop into transmissible sexual stages. Parasite commitment to gametocytogenesis is also an adaptive response to the host and ecological factors that affect transmission potential [5,107,108]. Our understanding of the transcriptional changes underlying this process and the epigenetic factors regulating them has grown in recent years [109,110]. ...
... The 3D chromatin structure of gametocytes differs substantially from their asexual counterparts [28]. Specifically, the TF ap2-g, expressed during the early stages of sexual commitment and essential for gametocytogenesis [5,109,110], was shown to interact strongly with repressive heterochromatin in asexual stages but dissociate from them in early gametocytes to reassociate in late-stage gametocytes [28]. The gametocyte development protein 1 gene (Pfgdv1) was discovered and shown to be mutated in a gametocyte-deficient laboratory parasite strain [111]. ...
The human malaria parasites, including Plasmodium falciparum, persist as a major cause of global morbidity and mortality. The recent stalling of progress toward malaria elimination substantiates a need for novel interventions. Controlled gene expression is central to the parasite's numerous life cycle transformations and adaptation. With few specific transcription factors (TFs) identified, crucial roles for chromatin states and epigenetics in parasite transcription have become evident. Although many chromatin-modifying enzymes are known, less is known about which factors mediate their impacts on transcriptional variation. Like those of higher eukaryotes, long noncoding RNAs (lncRNAs) have recently been shown to have integral roles in parasite gene regulation. This review aims to summarize recent developments and key findings on the role of lncRNAs in P. falciparum.
