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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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Related in: MedlinePlus

In vivo Pfge gene expression profiling.RNA from 20 gametocytemic patients was analyzed using a P. falciparum whole genome microarray. The color coded cluster analysis of the quantile normalized expression data for the Pfge genes with a G+/Gdef ratio>10 is shown with mature gametocyte specific genes Pfs25 and Pfs28 (Underlined in gray). The gene name and standardized intensity of the color code is indicated below and the patient cluster associated with high gametocytemia is indicated on the right with a vertical green bar. The gametocytemia (G'cyte) and asexual parasitemia (Asex) of the patient samples are represented both by color code and numerically on the right.
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ppat-1002964-g005: In vivo Pfge gene expression profiling.RNA from 20 gametocytemic patients was analyzed using a P. falciparum whole genome microarray. The color coded cluster analysis of the quantile normalized expression data for the Pfge genes with a G+/Gdef ratio>10 is shown with mature gametocyte specific genes Pfs25 and Pfs28 (Underlined in gray). The gene name and standardized intensity of the color code is indicated below and the patient cluster associated with high gametocytemia is indicated on the right with a vertical green bar. The gametocytemia (G'cyte) and asexual parasitemia (Asex) of the patient samples are represented both by color code and numerically on the right.

Mentions: The identification of genes that are specific for gametocyte-committed ring stage parasites provides an opportunity to evaluate whether these stages can be detected circulating in malaria patients and therefore be developed as biomarkers for gametocyte induction in vivo. Markers specific for early gametocytes could then be paired with mature stage V gametocytes markers, such as Pfs25[45], for use in future clinical studies to evaluate the parameters that affect gametocyte initiation and maturation. Since patient blood samples can contain both ring stage parasites and mature gametocytes it is important to identify genes that are expressed only in committed ring stage parasites, not mature gametocytes. In vitro culture is not a good model for this because it is difficult to separate immature from mature gametocytes, therefore we directly evaluated the expression profile of Pfgdv1 and the Pfge genes in a microarray analysis of samples obtained from 20 patients on the Thailand Myanmar border with a range of different gametocytemias and asexual parasitemias (Fig. 5 and Table S2).


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)

In vivo Pfge gene expression profiling.RNA from 20 gametocytemic patients was analyzed using a P. falciparum whole genome microarray. The color coded cluster analysis of the quantile normalized expression data for the Pfge genes with a G+/Gdef ratio>10 is shown with mature gametocyte specific genes Pfs25 and Pfs28 (Underlined in gray). The gene name and standardized intensity of the color code is indicated below and the patient cluster associated with high gametocytemia is indicated on the right with a vertical green bar. The gametocytemia (G'cyte) and asexual parasitemia (Asex) of the patient samples are represented both by color code and numerically on the right.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002964-g005: In vivo Pfge gene expression profiling.RNA from 20 gametocytemic patients was analyzed using a P. falciparum whole genome microarray. The color coded cluster analysis of the quantile normalized expression data for the Pfge genes with a G+/Gdef ratio>10 is shown with mature gametocyte specific genes Pfs25 and Pfs28 (Underlined in gray). The gene name and standardized intensity of the color code is indicated below and the patient cluster associated with high gametocytemia is indicated on the right with a vertical green bar. The gametocytemia (G'cyte) and asexual parasitemia (Asex) of the patient samples are represented both by color code and numerically on the right.
Mentions: The identification of genes that are specific for gametocyte-committed ring stage parasites provides an opportunity to evaluate whether these stages can be detected circulating in malaria patients and therefore be developed as biomarkers for gametocyte induction in vivo. Markers specific for early gametocytes could then be paired with mature stage V gametocytes markers, such as Pfs25[45], for use in future clinical studies to evaluate the parameters that affect gametocyte initiation and maturation. Since patient blood samples can contain both ring stage parasites and mature gametocytes it is important to identify genes that are expressed only in committed ring stage parasites, not mature gametocytes. In vitro culture is not a good model for this because it is difficult to separate immature from mature gametocytes, therefore we directly evaluated the expression profile of Pfgdv1 and the Pfge genes in a microarray analysis of samples obtained from 20 patients on the Thailand Myanmar border with a range of different gametocytemias and asexual parasitemias (Fig. 5 and Table S2).

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