Pleiotropic Roles for the Plasmodium berghei RNA Binding Protein UIS12 in Anopheles Transmission and Sporogony
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ABSTRACT:
ORGANISM(S): Plasmodium berghei
PROVIDER: GSE152686 | GEO | 2021/03/05
REPOSITORIES: GEO
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Project description:Male and female gametocytes are sexual precursor cells essential for transmission of malaria parasite in the mosquitoes. Differentiation of gametocytes to fertile gametes (gametogenesis) relies on the gender-specific transcriptome. However, how the parasites establish distinct repertoire of gene transcription in the male and female gametocytes remains largely unknown. Here, we report that an Apetala2 (AP2) family transcription factor (TF) AP2-O3 operates as a transcription repressor regulating female gametocyte transcriptome. AP2-O3 is specifically localized in the nucleus of the female gametocytes. AP2-O3-deficient parasites produce apparently normal female gametocytes, which fail to differentiate to fully fertile female gametes, leading to developmental arrest in fertilization and early development post-fertilization. AP2-O3 disruption causes massive up-regulation of transcriptionally dormant male genes and simultaneously down-regulation of highly transcribed female genes in female gametocytes. ChIP-seq and EMSA analysis establish AP2-O3 as a transcription repressor that targets a significant proportion of the upregulated male genes by recognizing an eight-base DNA motif in the promoters. In addition, the maternal AP2-O3 is removed after fertilization, which is required for the zygote to ookinete development. These results demonstrate that global transcriptional repression of male genes in the female gametocytes is required for safeguarding female-specific transcriptome and essential for the mosquito transmission of Plasmodium.
2021-01-26 | GSE157456 | GEO
Project description:Male and female gametocytes are sexual precursor cells essential for transmission of malaria parasite in the mosquitoes. Differentiation of gametocytes to fertile gametes (gametogenesis) relies on the gender-specific transcriptome. However, how the parasites establish distinct repertoire of gene transcription in the male and female gametocytes remains largely unknown. Here, we report that an Apetala2 (AP2) family transcription factor (TF) AP2-O3 operates as a transcription repressor regulating female gametocyte transcriptome. AP2-O3 is specifically localized in the nucleus of the female gametocytes. AP2-O3-deficient parasites produce apparently normal female gametocytes, which fail to differentiate to fully fertile female gametes, leading to developmental arrest in fertilization and early development post-fertilization. AP2-O3 disruption causes massive up-regulation of transcriptionally dormant male genes and simultaneously down-regulation of highly transcribed female genes in female gametocytes. ChIP-seq and EMSA analysis establish AP2-O3 as a transcription repressor that targets a significant proportion of the upregulated male genes by recognizing an eight-base DNA motif in the promoters. In addition, the maternal AP2-O3 is removed after fertilization, which is required for the zygote to ookinete development. These results demonstrate that global transcriptional repression of male genes in the female gametocytes is required for safeguarding female-specific transcriptome and essential for the mosquito transmission of Plasmodium.
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Project description:Transmission of malaria is dependent on the successful completion of the Plasmodium lifecycle in the Anopheles vector. Major obstacles are encountered in the midgut tissue, where most parasites are killed by the mosquito’s immune system. In the present study, DNA microarray analyses have been used to compare Anopheles gambiae responses to invasion of the midgut epithelium by the ookinete stage of the human pathogen Plasmodium falciparum and the rodent experimental model pathogen P. berghei. Invasion by P. berghei had a more profound impact on the mosquito transcriptome, including a variety of functional gene classes, while P. falciparum elicited a broader immune response at the gene transcript level. Ingestion of human malaria-infected blood lacking invasive ookinetes also induced a variety of immune genes, including several anti-Plasmodium factors. Keywords: Anopheles gambiae, Plasmodium falciparum, ookinete, invasion, innate immunity
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Project description:Plasmodium, the malaria parasite, undergoes a complex life cycle, which alternates between a vertebrate host and a mosquito vector of the genus Anopheles. In red blood cells of the vertebrate host, Plasmodium multiplies asexually or differentiates into gamete precursors, the male and female gametocytes, responsible for parasite transmission. Sexual stage maturation occurs in the midgut of the mosquito vector, where male and female gametes egress from the host erythrocyte to form a zygote. Gamete egress entails the successive rupture of two membranes surrounding the parasite, the parasitophorous vacuole membrane and the erythrocyte plasma membrane.
In this study, we applied a proteomic approach to identify proteins differentially released/secreted by female and male gametocytes of the rodent Plasmodium berghei activated to form gametes. We compared secreted molecules of the wild type gametocytes with those of a transgenic line defective in male gamete maturation and egress. This enabled us to provide a comprehensive dataset of egress-related molecules and their gender specificity. Using specific antibodies, we validated eleven candidate molecules, predicted as either gender-specific or common to both male and female gametocytes. All of them localize to punctuate, vesicle-like structures that relocate to cell periphery upon activation, but only three of them localize to the gametocyte-specific secretory vesicles named osmiophilic bodies. Our results confirm that the egress process involves a tightly coordinated secretory apparatus that includes different types of vesicles and may put the basis for functional studies aimed at designing novel transmission-blocking molecules.
2020-06-30 | MSV000085650 | MassIVE
Project description:Plasmodium falciparum parasites alternate between two different obligate hosts during their life cycle: humans and Anopheles mosquitoes. During the blood stage in the human host they proliferate asexually inside erythrocytes. A small proportion of parasites develops into male and female gametocytes, which enter the sexual part of the life cycle once taken up by a mosquito. The production of male and female gametocytes is therefore critical for malaria transmission. It has been shown that epigenetic processes play a role in this differentiation processes, however, the exact mechanisms remain unknown. To gain insight into these processes, we separated male and female gametocytes, based on the female specific expression of an endogenously GFP-tagged ABCG2 gene, using flow cytometry (male parasites as GFP low, female parasites as GFP high population). We subsequently performed ChIP-Seq for several histone variants and modifications (H2A.Z, H2A.Zac, H2B.Z, H3K4me3, H3R17me2, H3K27ac, H3K9me3) on day 6 of gametocytogenesis. Our study reveals a global remodelling of the chromatin landscape in gametocytes compared to asexual parasites, as well as sex specific differences.
2022-05-07 | GSE202214 | GEO
Project description:During the malaria infection, Plasmodium parasites invade the host’s red blood cells where they can differentiate into two different life forms. The majority will replicate asexually and infect new erythrocytes. A small percentage, however, will transform into gametocytes – a specialized sexual stage able to survive and develop when taken up by Anopheles mosquito. As the gametocytes ensure the parasite’s transmission to a new host, their generation is an attractive target for new antimalarial interventions. The molecular mechanisms controlling gametocytogenesis, however, remain largely unknown due to the technical challenges: the early gametocytes are morphologically indistinguishable from asexual parasites and present in very low numbers during the infection. Recently, AP2-G - a transcription factor from an apicomplexa-specific apiAP2 family – was described as indispensable for gametocyte commitment in both human malaria parasite Plasmodium falciparum and rodent malaria model Plasmodium berghei. Therefore, we have decided to test whether the overexpression of this factor alone could increase gametocyte production and enable the investigation of uncharacterised, earliest stages of gametocyte development. To this end, we have engineered PBGAMi - a Plasmodium berghei line, in which all parasites were ap2-g deficient by default but able to overexpress it when induced with rapamycin. While the control parasites (PBGAMi R-), as expected, differentiated into asexual forms (schizonts) only, almost all rapamycin-treated parasites (PBGAMi R+) transformed into gametocytes. We used the generated line to perform RNA-seq analysis of the R- and R+ populations at different time points of their development and identify the changes arising between them, mapping the sequence of events leading to the formation of gametocytes.
2018-06-30 | GSE110201 | GEO
Project description:Transmission of malaria is dependent on the successful completion of the Plasmodium lifecycle in the Anopheles vector. Major obstacles are encountered in the midgut tissue, where most parasites are killed by the mosquito’s immune system. In the present study, DNA microarray analyses have been used to compare Anopheles gambiae responses to invasion of the midgut epithelium by the ookinete stage of the human pathogen Plasmodium falciparum and the rodent experimental model pathogen P. berghei. Invasion by P. berghei had a more profound impact on the mosquito transcriptome, including a variety of functional gene classes, while P. falciparum elicited a broader immune response at the gene transcript level. Ingestion of human malaria-infected blood lacking invasive ookinetes also induced a variety of immune genes, including several anti-Plasmodium factors. By comparing gene expression patterns between carcassess or guts of mosquitoes that fed on a P. falciparum or P. berghei wt and mosquitoes that fed on invasion incapable strains we gain information on the A. gambiae transcriptional responses to the invading ookinete at 24 hours after feeding. By comparing gene expression patterns between carcassess or guts of mosquitoes that fed on a P. falciparum ookinete invasion incapable strain and mosquitoes that fed on non-infected blood we gain information on the A. gambiae transcriptional responses to malaria infected blood in absence of ookinete invasion at 24 hours after feeding. By comparing gene expression patterns between mosquitoes at 4 hours after being injected with either E. coli or S. aureus and mosquitoes injected with sterile PBS we gain information on the mosquito's transcriptional response to these bacterial challenges.
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Project description:During the malaria infection, Plasmodium parasites invade the host’s red blood cells where they can differentiate into two different life forms. The majority will replicate asexually and infect new erythrocytes. A small percentage, however, will transform into gametocytes – a specialized sexual stage able to survive and develop when taken up by Anopheles mosquito. As the gametocytes ensure the parasite’s transmission to a new host, their generation is an attractive target for new antimalarial interventions. The molecular mechanisms controlling gametocytogenesis, however, remain largely unknown due to the technical challenges: the early gametocytes are morphologically indistinguishable from asexual parasites and present in very low numbers during the infection. Recently, AP2-G - a transcription factor from an apicomplexa-specific apiAP2 family – was described as indispensable for gametocyte commitment in both human malaria parasite Plasmodium falciparum and rodent malaria model Plasmodium berghei. Therefore, we have decided to test whether the overexpression of this factor alone could increase gametocyte production and enable the investigation of uncharacterised, earliest stages of gametocyte development. To this end, we have engineered PBGAMi - a Plasmodium berghei line, in which all parasites were ap2-g deficient by default but able to overexpress it when induced with rapamycin. While the control parasites (PBGAMi R-), as expected, differentiated into asexual forms (schizonts) only, almost all rapamycin-treated parasites (PBGAMi R+) transformed into gametocytes. We used the generated line to perform RNA-seq analysis of the R- and R+ populations at different time points of their development and identify the changes arising between them, mapping the sequence of events leading to the formation of gametocytes. At the same time we have generated purified transcriptomes of male and female gametocytes for the reference
2021-03-13 | GSE168817 | GEO
Project description:Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is mediated by the intraerythrocytic gametocytes, which, once taken up during a blood meal, become activated to initiate sexual reproduction. Because gametocytes are the only parasite stages able to establish an infection in the mosquito, they are crucial for spreading the tropical disease. During gametocyte maturation, different repertoires of genes are switched on and off in a well-coordinated sequence, pointing to regulatory mechanisms of gene expression. While epigenetic gene control has been studied during erythrocytic schizogony of P. falciparum, little is known about this process during parasite human-to-mosquito transmission of the parasite. To unveil the potential role of histone acetylation during gene expression in gametocytes, we carried out a microarray-based transcriptome analysis on gametocytes treated with the histone deacetylase inhibitor trichostatin A (TSA).
2017-05-24 | GSE99223 | GEO