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Targeting Human Transmission Biology for Malaria Elimination.

Nilsson SK, Childs LM, Buckee C, Marti M - PLoS Pathog. (2015)

Bottom Line: Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods.Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop.We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

ABSTRACT
Malaria remains one of the leading causes of death worldwide, despite decades of public health efforts. The recent commitment by many endemic countries to eliminate malaria marks a shift away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods. Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop. We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.

No MeSH data available.


Related in: MedlinePlus

Commitment to sexual maturation.During each asexual cycle within the human blood, a small proportion of parasites cease to replicate asexually and instead produce sexual progeny that develop into nonreplicating gametocytes, capable of onward transmission to the mosquito vector. Commitment to the sexual pathway occurs at a low “baseline” rate during each asexual replication cycle [14,15], and the decision to switch is thought to be made prior to schizogony during the previous asexual replication cycle [10–12]. The switch to gametocytogenesis is governed by the essential transcription factor PfAP2-G (Box 2), which is epigenetically controlled byPfHda2 and PfHP1 [16,17]. PfHda2 likely promotes transcriptional silencing by removing acetyl groups on histones, thereby allowing methylation of histone 3 lysine 9 (H3K9). PfHP1 may subsequently bind H3K9me, leading to heterochromatin formation and Pfap2-g repression. The perinuclear protein Pfgdv1 is another key player that likely operates upstream of PfAP2-G. Pfgdv1 is expressed in a subset of schizonts, is associated with an increased expression of genes involved in early gametocytogenesis, and has been shown to be critical for gametocyte production [18]. The Nima-related kinase Pfnek4 may also play a role in sexual commitment, as the kinase is expressed in a subpopulation of schizonts that display a higher sexual conversion rate [19]. Pfnek4 is, however, not strictly gametocyte specific and can be genetically deleted without affecting gametocyte formation [19]. Although constitutively silenced in asexual parasites, Pfap2-g could be prone to stochastic activation, resulting in a low level of gametocyte formation. Once initiated, the transcription of Pfap2-g may be further activated via a positive feedback loop. The baseline conversion rate can be altered by various factors: those that are derived from the parasites themselves (found within conditioned medium from high-parasitemia in vitro cultures) and those that are exogenous (antimalarial drugs, anemia, elevated reticulocyte levels, and host immune factors). Enhanced conversion by external factors is extensively reviewed elsewhere [27]. It has recently been demonstrated that the conditioned medium effect is the result of cellular communication within the parasite population via pRBC-derived microvesicles (Box 3) [24,25].
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ppat.1004871.g002: Commitment to sexual maturation.During each asexual cycle within the human blood, a small proportion of parasites cease to replicate asexually and instead produce sexual progeny that develop into nonreplicating gametocytes, capable of onward transmission to the mosquito vector. Commitment to the sexual pathway occurs at a low “baseline” rate during each asexual replication cycle [14,15], and the decision to switch is thought to be made prior to schizogony during the previous asexual replication cycle [10–12]. The switch to gametocytogenesis is governed by the essential transcription factor PfAP2-G (Box 2), which is epigenetically controlled byPfHda2 and PfHP1 [16,17]. PfHda2 likely promotes transcriptional silencing by removing acetyl groups on histones, thereby allowing methylation of histone 3 lysine 9 (H3K9). PfHP1 may subsequently bind H3K9me, leading to heterochromatin formation and Pfap2-g repression. The perinuclear protein Pfgdv1 is another key player that likely operates upstream of PfAP2-G. Pfgdv1 is expressed in a subset of schizonts, is associated with an increased expression of genes involved in early gametocytogenesis, and has been shown to be critical for gametocyte production [18]. The Nima-related kinase Pfnek4 may also play a role in sexual commitment, as the kinase is expressed in a subpopulation of schizonts that display a higher sexual conversion rate [19]. Pfnek4 is, however, not strictly gametocyte specific and can be genetically deleted without affecting gametocyte formation [19]. Although constitutively silenced in asexual parasites, Pfap2-g could be prone to stochastic activation, resulting in a low level of gametocyte formation. Once initiated, the transcription of Pfap2-g may be further activated via a positive feedback loop. The baseline conversion rate can be altered by various factors: those that are derived from the parasites themselves (found within conditioned medium from high-parasitemia in vitro cultures) and those that are exogenous (antimalarial drugs, anemia, elevated reticulocyte levels, and host immune factors). Enhanced conversion by external factors is extensively reviewed elsewhere [27]. It has recently been demonstrated that the conditioned medium effect is the result of cellular communication within the parasite population via pRBC-derived microvesicles (Box 3) [24,25].

Mentions: What factors activate the Apicomplexan Apetala 2 (ApiAP2)-mediated sexual conversion pathway (Fig 2)?


Targeting Human Transmission Biology for Malaria Elimination.

Nilsson SK, Childs LM, Buckee C, Marti M - PLoS Pathog. (2015)

Commitment to sexual maturation.During each asexual cycle within the human blood, a small proportion of parasites cease to replicate asexually and instead produce sexual progeny that develop into nonreplicating gametocytes, capable of onward transmission to the mosquito vector. Commitment to the sexual pathway occurs at a low “baseline” rate during each asexual replication cycle [14,15], and the decision to switch is thought to be made prior to schizogony during the previous asexual replication cycle [10–12]. The switch to gametocytogenesis is governed by the essential transcription factor PfAP2-G (Box 2), which is epigenetically controlled byPfHda2 and PfHP1 [16,17]. PfHda2 likely promotes transcriptional silencing by removing acetyl groups on histones, thereby allowing methylation of histone 3 lysine 9 (H3K9). PfHP1 may subsequently bind H3K9me, leading to heterochromatin formation and Pfap2-g repression. The perinuclear protein Pfgdv1 is another key player that likely operates upstream of PfAP2-G. Pfgdv1 is expressed in a subset of schizonts, is associated with an increased expression of genes involved in early gametocytogenesis, and has been shown to be critical for gametocyte production [18]. The Nima-related kinase Pfnek4 may also play a role in sexual commitment, as the kinase is expressed in a subpopulation of schizonts that display a higher sexual conversion rate [19]. Pfnek4 is, however, not strictly gametocyte specific and can be genetically deleted without affecting gametocyte formation [19]. Although constitutively silenced in asexual parasites, Pfap2-g could be prone to stochastic activation, resulting in a low level of gametocyte formation. Once initiated, the transcription of Pfap2-g may be further activated via a positive feedback loop. The baseline conversion rate can be altered by various factors: those that are derived from the parasites themselves (found within conditioned medium from high-parasitemia in vitro cultures) and those that are exogenous (antimalarial drugs, anemia, elevated reticulocyte levels, and host immune factors). Enhanced conversion by external factors is extensively reviewed elsewhere [27]. It has recently been demonstrated that the conditioned medium effect is the result of cellular communication within the parasite population via pRBC-derived microvesicles (Box 3) [24,25].
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4472755&req=5

ppat.1004871.g002: Commitment to sexual maturation.During each asexual cycle within the human blood, a small proportion of parasites cease to replicate asexually and instead produce sexual progeny that develop into nonreplicating gametocytes, capable of onward transmission to the mosquito vector. Commitment to the sexual pathway occurs at a low “baseline” rate during each asexual replication cycle [14,15], and the decision to switch is thought to be made prior to schizogony during the previous asexual replication cycle [10–12]. The switch to gametocytogenesis is governed by the essential transcription factor PfAP2-G (Box 2), which is epigenetically controlled byPfHda2 and PfHP1 [16,17]. PfHda2 likely promotes transcriptional silencing by removing acetyl groups on histones, thereby allowing methylation of histone 3 lysine 9 (H3K9). PfHP1 may subsequently bind H3K9me, leading to heterochromatin formation and Pfap2-g repression. The perinuclear protein Pfgdv1 is another key player that likely operates upstream of PfAP2-G. Pfgdv1 is expressed in a subset of schizonts, is associated with an increased expression of genes involved in early gametocytogenesis, and has been shown to be critical for gametocyte production [18]. The Nima-related kinase Pfnek4 may also play a role in sexual commitment, as the kinase is expressed in a subpopulation of schizonts that display a higher sexual conversion rate [19]. Pfnek4 is, however, not strictly gametocyte specific and can be genetically deleted without affecting gametocyte formation [19]. Although constitutively silenced in asexual parasites, Pfap2-g could be prone to stochastic activation, resulting in a low level of gametocyte formation. Once initiated, the transcription of Pfap2-g may be further activated via a positive feedback loop. The baseline conversion rate can be altered by various factors: those that are derived from the parasites themselves (found within conditioned medium from high-parasitemia in vitro cultures) and those that are exogenous (antimalarial drugs, anemia, elevated reticulocyte levels, and host immune factors). Enhanced conversion by external factors is extensively reviewed elsewhere [27]. It has recently been demonstrated that the conditioned medium effect is the result of cellular communication within the parasite population via pRBC-derived microvesicles (Box 3) [24,25].
Mentions: What factors activate the Apicomplexan Apetala 2 (ApiAP2)-mediated sexual conversion pathway (Fig 2)?

Bottom Line: Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods.Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop.We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

ABSTRACT
Malaria remains one of the leading causes of death worldwide, despite decades of public health efforts. The recent commitment by many endemic countries to eliminate malaria marks a shift away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods. Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop. We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.

No MeSH data available.


Related in: MedlinePlus