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Plasmodium falciparum gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development.

Eksi S, Morahan BJ, Haile Y, Furuya T, Jiang H, Ali O, Xu H, Kiattibutr K, Suri A, Czesny B, Adeyemo A, Myers TG, Sattabongkot J, Su XZ, Williamson KC - PLoS Pathog. (2012)

Bottom Line: Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut.Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation.The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Loyola University Chicago, Chicago, Illinois, USA.

ABSTRACT
Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.

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Model for continuous gametocytogenesis.During each round of the asexual cycle, a proportion of the schizonts (Sc, light blue) produced are committed to producing merozoites (Mc, light blue) that will differentiate into gametocytes (Gc, GI–V) after invading a RBC. The expression profile for Pfgdv1 is indicated by a line under the corresponding stage.
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ppat-1002964-g006: Model for continuous gametocytogenesis.During each round of the asexual cycle, a proportion of the schizonts (Sc, light blue) produced are committed to producing merozoites (Mc, light blue) that will differentiate into gametocytes (Gc, GI–V) after invading a RBC. The expression profile for Pfgdv1 is indicated by a line under the corresponding stage.

Mentions: The expression of Pfgdv1 and the Pfge genes through multiple rounds of asexual growth of strain 3D7 parasites and continued expression for 24 hours after the clearance of asexual parasites is in marked contradiction to the hypothesis that gametocyte differentiation is induced by the same stress imposed by high density culture that inhibits further asexual growth. Additionally, blocking the development of high parasitemia on day 7 using NAG did not affect gametocyte production. However, other parasite strains will have to be tested to determine if this is a general characteristic. These data suggest that in strain 3D7 parasites, a subpopulation of parasites convert to gametocytogenesis during each asexual cycle, instead of a model where the majority of parasites differentiate in response to a onetime stimulation event as seen in yeast after exposure to stress-induced mating pheromone, a quorum response in bacteria to high cell levels, or induction factor stimulation of trypanosomes [13], [59]–[62]. The ongoing conversion of a subpopulation of intraerythrocytic parasites to sexual differentiation during each asexual cycle fits well with the pattern of gametocyte production observed in neurosyphilis patients receiving malaria therapy [63], [64]. During the long course of malaria therapy, the rise of circulating stage V gametocytes follows the same pattern as the increase in asexual parasitemia, but is delayed by the 10 days required for gametocyte maturation and plateaus at ∼10% of the maximal asexual parasitemia. These findings suggest that during each asexual cycle ∼10% of the parasites are committed to gametocytogenesis (Fig. 6). This ratio is similar to the gametocyte conversion rate reported for P. vivax[65], and the ratio of ring stage parasites to stage II gametocytes observed in our in vitro cultures (13.35%±0.175, mean ± SEM), suggesting a consistent sexual induction rate in vitro and in vivo. A model of continuous gametocyte induction during each asexual erythrocytic cycle is also supported by the significant correlation found between Pfge1 expression levels with asexual parasitemia in patients in the current study and previous reports that gametocytes can be detected in >90% of malaria patients when analyzed by quantitative-nucleic acid sequence-based amplification [63], [64]. The continuous differentiation of a subpopulation of progeny from a reservoir of self-renewing stem cells seen in sperm formation or hematopoiesis may be a better model for gametocytogenesis than sexual differentiation in yeast [66], [67]. Such a strategy of ongoing gametocyte production could facilitate transmission by providing a continuous source of infectious gametocytes whenever a mosquito takes a blood meal.


Plasmodium falciparum gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development.

Eksi S, Morahan BJ, Haile Y, Furuya T, Jiang H, Ali O, Xu H, Kiattibutr K, Suri A, Czesny B, Adeyemo A, Myers TG, Sattabongkot J, Su XZ, Williamson KC - PLoS Pathog. (2012)

Model for continuous gametocytogenesis.During each round of the asexual cycle, a proportion of the schizonts (Sc, light blue) produced are committed to producing merozoites (Mc, light blue) that will differentiate into gametocytes (Gc, GI–V) after invading a RBC. The expression profile for Pfgdv1 is indicated by a line under the corresponding stage.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475683&req=5

ppat-1002964-g006: Model for continuous gametocytogenesis.During each round of the asexual cycle, a proportion of the schizonts (Sc, light blue) produced are committed to producing merozoites (Mc, light blue) that will differentiate into gametocytes (Gc, GI–V) after invading a RBC. The expression profile for Pfgdv1 is indicated by a line under the corresponding stage.
Mentions: The expression of Pfgdv1 and the Pfge genes through multiple rounds of asexual growth of strain 3D7 parasites and continued expression for 24 hours after the clearance of asexual parasites is in marked contradiction to the hypothesis that gametocyte differentiation is induced by the same stress imposed by high density culture that inhibits further asexual growth. Additionally, blocking the development of high parasitemia on day 7 using NAG did not affect gametocyte production. However, other parasite strains will have to be tested to determine if this is a general characteristic. These data suggest that in strain 3D7 parasites, a subpopulation of parasites convert to gametocytogenesis during each asexual cycle, instead of a model where the majority of parasites differentiate in response to a onetime stimulation event as seen in yeast after exposure to stress-induced mating pheromone, a quorum response in bacteria to high cell levels, or induction factor stimulation of trypanosomes [13], [59]–[62]. The ongoing conversion of a subpopulation of intraerythrocytic parasites to sexual differentiation during each asexual cycle fits well with the pattern of gametocyte production observed in neurosyphilis patients receiving malaria therapy [63], [64]. During the long course of malaria therapy, the rise of circulating stage V gametocytes follows the same pattern as the increase in asexual parasitemia, but is delayed by the 10 days required for gametocyte maturation and plateaus at ∼10% of the maximal asexual parasitemia. These findings suggest that during each asexual cycle ∼10% of the parasites are committed to gametocytogenesis (Fig. 6). This ratio is similar to the gametocyte conversion rate reported for P. vivax[65], and the ratio of ring stage parasites to stage II gametocytes observed in our in vitro cultures (13.35%±0.175, mean ± SEM), suggesting a consistent sexual induction rate in vitro and in vivo. A model of continuous gametocyte induction during each asexual erythrocytic cycle is also supported by the significant correlation found between Pfge1 expression levels with asexual parasitemia in patients in the current study and previous reports that gametocytes can be detected in >90% of malaria patients when analyzed by quantitative-nucleic acid sequence-based amplification [63], [64]. The continuous differentiation of a subpopulation of progeny from a reservoir of self-renewing stem cells seen in sperm formation or hematopoiesis may be a better model for gametocytogenesis than sexual differentiation in yeast [66], [67]. Such a strategy of ongoing gametocyte production could facilitate transmission by providing a continuous source of infectious gametocytes whenever a mosquito takes a blood meal.

Bottom Line: Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut.Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation.The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Loyola University Chicago, Chicago, Illinois, USA.

ABSTRACT
Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.

Show MeSH
Related in: MedlinePlus