A Central Role for P48/45 in Malaria Parasite Male Gamete Fertility

Dijk, Melissa R. van; Janse, Chris J.; Thompson, Joanne; Waters, Andrew P.; Braks, Joanna A. M.; Dodemont, H.; Stunnenberg, Henk; Gemert, Geert-Jan van; Sauerwein, Robert W.; Eling, W.M.C.

doi:10.1016/s0092-8674(01)00199-4

Cited by 360 publications

(356 citation statements)

References 48 publications

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“…Where studied, expression of members of this family was restricted to sexual erythrocytic stages. Recently, targeted gene disruption of P48͞45 identified the protein as a male gamete fertility factor (47). We have identified Py52 and Pf52 as genes coding for new members of the 6-cys family.…”

Section: Discussionmentioning

confidence: 99%

Exploring the transcriptome of the malaria sporozoite stage

Kappe

Gardner

Brown

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

125

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Most studies of gene expression in Plasmodium have been concerned with asexual and͞or sexual erythrocytic stages. Identification and cloning of genes expressed in the preerythrocytic stages lag far behind. We have constructed a high quality cDNA library of the Plasmodium sporozoite stage by using the rodent malaria parasite P. yoelii, an important model for malaria vaccine development. The technical obstacles associated with limited amounts of RNA material were overcome by PCR-amplifying the transcriptome before cloning. Contamination with mosquito RNA was negligible. Generation of 1,972 expressed sequence tags (EST) resulted in a total of 1,547 unique sequences, allowing insight into sporozoite gene expression. The circumsporozoite protein (CS) and the sporozoite surface protein 2 (SSP2) are well represented in the data set. A BLASTX search with all tags of the nonredundant protein database gave only 161 unique significant matches (P(N) < 10 ؊4 ), whereas 1,386 of the unique sequences represented novel sporozoite-expressed genes. We identified ESTs for three proteins that may be involved in host cell invasion and documented their expression in sporozoites. These data should facilitate our understanding of the preerythrocytic Plasmodium life cycle stages and the development of preerythrocytic vaccines.Plasmodium yoelii yoelii ͉ expressed sequence tag P rotozoan parasites of the genus Plasmodium are the causative agents of malaria, the most devastating parasitic disease in humans. The parasites occur in distinct morphological and antigenic stages as they progress through a complex life cycle, thwarting decades of efforts to develop an effective malaria vaccine. Plasmodium is transmitted via the bite of an infected Anopheles mosquito, which releases the sporozoite stage into the skin. Sporozoites enter the bloodstream and, on reaching the liver, invade hepatocytes and develop into exo-erythrocytic forms (EEF). After multiple cycles of DNA replication, the EEF contains thousands of merozoites (liver schizont) that are released into the blood stream and initiate the erythrocytic cycle (asexual blood stage) that causes the disease malaria. Changes in life cycle stages are accompanied by major changes in gene expression and therefore by major changes in antigenic composition. The form of the parasite best studied is the asexual blood stage, mainly because of its comparatively easy experimental accessibility. Therefore, most Plasmodium proteins that have been well characterized are expressed during the erythrocytic cycle, among them some major erythrocytic-stage vaccine candidates such as merozoite surface protein-1 (MSP-1) and apical membrane antigen-1 (AMA-1; ref. 1). Erythrocytic-stage vaccines are aimed at inducing an immune response that suppresses or eradicates parasite load in the blood. In contrast, preerythrocytic vaccines are aimed at eliciting an immune response that destroys the sporozoites and the EEF, thereby preventing progression of the parasite to the blood stage. The feasibility of a preerythrocytic v...

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Section: Discussionmentioning

confidence: 99%

Exploring the transcriptome of the malaria sporozoite stage

Kappe

Gardner

Brown

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

125

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“…Several proteins have been linked to microgamete attachment to macrogametes, including the LCCL‐domain proteins (termed CCp proteins in P . falciparum ) and the six‐cys motif proteins Ps47, Ps48/45 and Ps230 (van Dijk et al ., 2001; Pradel et al ., 2004; van Schaijk et al ., 2006; Simon et al ., 2009, 2016). The latter two are considered as promising candidates for transmission blocking vaccines (reviewed in Pradel, 2007).…”

Section: The Formation Of Gametesmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

163

155

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SummaryThe mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.

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“…Microgametocytes differentiate into eight sperm-like microgametes, each capable of fertilizing a macrogamete. In Plasmodium berghei, a malaria parasite infecting rodents, gamete adhesion is dependent on the Plasmodium-specific P48/45 and P47 gamete surface proteins (van Dijk et al 2001).…”

mentioning

confidence: 99%

Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates

et al. 2013

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Fertilization is a crucial yet poorly characterized event in eukaryotes. Our previous discovery that the broadly conserved protein HAP2 (GCS1) functioned in gamete membrane fusion in the unicellular green alga Chlamydomonas and the malaria pathogen Plasmodium led us to exploit the rare biological phenomenon of isogamy in Chlamydomonas in a comparative transcriptomics strategy to uncover additional conserved sexual reproduction genes. All previously identified Chlamydomonas fertilization-essential genes fell into related clusters based on their expression patterns. Out of several conserved genes in a minus gamete cluster, we focused on Cre06.g280600, an ortholog of the fertilization-related Arabidopsis GEX1. Gene disruption, cell biological, and immunolocalization studies show that CrGEX1 functions in nuclear fusion in Chlamydomonas. Moreover, CrGEX1 and its Plasmodium ortholog, PBANKA_113980, are essential for production of viable meiotic progeny in both organisms and thus for mosquito transmission of malaria. Remarkably, we discovered that the genes are members of a large, previously unrecognized family whose first-characterized member, KAR5, is essential for nuclear fusion during yeast sexual reproduction. Our comparative transcriptomics approach provides a new resource for studying sexual development and demonstrates that exploiting the data can lead to the discovery of novel biology that is conserved across distant taxa.

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A Central Role for P48/45 in Malaria Parasite Male Gamete Fertility

Cited by 360 publications

References 48 publications

Exploring the transcriptome of the malaria sporozoite stage

Exploring the transcriptome of the malaria sporozoite stage

The development of malaria parasites in the mosquito midgut

Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates

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