The gametocyte‐activating factor xanthurenic acid stimulates an increase in membrane‐associated guanylyl cyclase activity in the human malaria parasite <i>Plasmodium falciparum</i>

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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“…XA, however, was shown to trigger guanylyl cyclase activity in gametocyte membranes (Muhia et al ., 2001). In P .…”

Section: The Initiation Of Gametogenesismentioning

confidence: 99%

“…Ca 2+ , on the other hand, was shown to inhibit guanylyl cyclase activity (Muhia et al ., 2001). In eukaryotic cells, the intracellular cGMP concentrations are generally regulated by cGMP‐synthetizing guanylyl cyclases and cGMP‐hydrolyzing phosphodiesterases (PDE).…”

Section: The Initiation Of Gametogenesismentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

167

155

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“…Once in the mosquito midgut, the intraerythrocytic gametocytes sense the change of hosts due to the perception of environmental factors present in the gut lumen, triggering their egress from the RBC and their transformation into gametes. Initially, a plasmodial guanylyl cyclase becomes activated, leading to the synthesis of cyclic GMP (cGMP) (Carucci et al, 2000;Muhia et al, 2001). The rise of cGMP activates the cGMP-dependent protein kinase G, which regulates the generation of PIP 2 (Alam et al, 2015;Brochet et al, 2014;McRobert et al, 2008).…”

Section: The Role Of Plasmodial Phospholipases During Life-cycle Progmentioning

confidence: 99%

Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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A B S T R A C TPlasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.

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“…For Plasmodium , an in vitro fertilization (IVF) assay has been established involving three factors required to induce gametogenesis: (1) a drop in temperature from 37 °C to 21 °C; (2) the presence of xanthurenic acid (XA), a previously determined mosquito-derived factor (Billker et al 1998 ); and (3) alkaline conditions (pH 8.0). Through IVF, it has been demonstrated that XA activates membrane-bound guanylate cyclase (GC) (Muhia et al 2001 ) and cGMP-dependent protein kinase (PKG) (McRobert et al 2008 ), which are essential for male exfl agellation. Moreover, N -methyl-hydroxylamine, an inhibitor of GC, inhibits exfl agellation (Kawamoto et al 1990 ).…”

Section: Sexual Differentiation and Gametogenesis Of Malaria Parasitesmentioning

confidence: 99%

Fertilization Mechanisms of the Rodent Malarial Parasite Plasmodium berghei

Hirai

2014

Sexual Reproduction in Animals and Plants

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Malaria, caused by Plasmodium spp., is transmitted by anopheline mosquitoes. When male and female gametes are introduced into the mosquito midgut, they reproduce sexually and proliferate, at which time the mosquito becomes infectious to vertebrates. It has been proposed that fertilization is a critical target in the parasite life cycle for the reduction of malarial prevalence. Although understanding parasite fertilization is crucial for the control of malaria, the precise molecular mechanisms involved have long remained unknown. Generative cell-specifi c 1 (GCS1) has been reported to be a critical fertilization factor in angiosperms. It was subsequently shown that the function of GCS1 is conserved in both the rodent malaria parasite Plasmodium berghei and the green alga Chlamydomonas reinhardtii . Moreover, a GCS1 -like gene has been detected in the genomes of various organisms, suggesting that it plays a conserved role in gamete interaction. As GCS1 is thought to act as a membrane-anchoring protein in male gametes, a female counterpart is assumed to exist. To reveal the mechanisms involved in parasite fertilization, it is important to clarify the function of GCS1 and to identify GCS1 partners and other fertilization factors. In this review, I fi rst describe the life cycle of malaria parasites, focusing on gametogenesis and fertilization and the underlying mechanisms. I then discuss the functions of GCS1 at the time of gamete interaction. Finally, I consider whether parasite fertilization factors, including GCS1, might be utilized in the development of antimalarial vaccines.

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The gametocyte‐activating factor xanthurenic acid stimulates an increase in membrane‐associated guanylyl cyclase activity in the human malaria parasite Plasmodium falciparum

Cited by 82 publications

References 33 publications

The development of malaria parasites in the mosquito midgut

The development of malaria parasites in the mosquito midgut

Phospholipases during membrane dynamics in malaria parasites

Fertilization Mechanisms of the Rodent Malarial Parasite Plasmodium berghei

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