A calcium‐dependent protein kinase regulates <i>Plasmodium</i> ookinete access to the midgut epithelial cell

Ishino, Tomoko; Orito, Yuki; Chinzei, Yasuo; Yuda, Masao

doi:10.1111/j.1365-2958.2005.05014.x

Cited by 205 publications

(201 citation statements)

References 28 publications

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“…Also, the activity of CDPK3 is required for P . berghei ookinete motility and engagement with the mosquito midgut epithelium (Ishino et al ., 2006; Siden‐Kiamos et al ., 2006), suggesting that besides cGMP, Ca 2+ is important for ookinete motility. In accord with these findings, quantitative phosphoproteomics comparing P .…”

Section: The Zygote‐to‐ookinete Conversionmentioning

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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Section: The Zygote‐to‐ookinete Conversionmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

163

155

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“…We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC 50 values of ∼100 nM, values at least 22-fold more potent than their apparent IC 50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle.…”

mentioning

confidence: 99%

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Malmquist

Moss

Mécheri

et al. 2012

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

119

116

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Epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC 50 values of ∼100 nM, values at least 22-fold more potent than their apparent IC 50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle. Decrease in parasite viability (>40%) was seen after a 3-h incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a 12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced parasitemia the following day. Importantly, treatment of P. falciparum parasites in culture with BIX-01294 or TM2-115 resulted in significant reductions in histone H3K4me3 levels in a concentration-dependent and exposure time-dependent manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Our data position histone lysine methyltransferases as a previously unrecognized target class, and BIX-01294 as a promising lead compound, in a presently unexploited avenue for antimalarial drug discovery targeting multiple life-cycle stages.chromatin | global health | chemical genetics M alaria continues to claim >1 million lives annually, particularly in the vulnerable populations of pregnant women and children <5 y of age (1, 2). Although artemisinin-based combination therapies have helped rescue the world's antimalarial armamentarium, the parasite's ability to develop resistance continues to outpace our ability to control this devastating disease (3). Effective malaria drug discovery efforts must therefore include both the development of improved antimalarials from existing compounds and the discovery of new parasite drug targets and novel small-molecule inhibitors.Epigenetic control of gene regulation in Plasmodium falciparum, the main causative agent of human malaria, has received considerable attention originally due to the apparent lack of recognizable transcription factors in the parasite genome (4). Although the recent discovery of a family of apicomplexan AP2 transcription factors (5, 6) has partly fulfilled the search for more traditional transcription factors, epigenetic gene regulation, particularly at the level of histone posttranslational modifications, has proven to play a significant role in P. falciparum virulence gene regulation. For example, expression of variant surface antigen gene families (7) and ligands involved in parasite red bl...

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“…The initial steps of sporogony following fertilisation in P. berghei require Pbnek-4, a NIMA-related kinase with a role in meiosis (Reininger et al, 2005), and a second enzyme of this family was recently shown to also be essential for meiosis in both P. berghei and P. falciparum (Reininger et al, 2009). PbCDPK3 is required for traversal of the mosquito midgut epithelium (Ishino et al, 2006;SidenKiamos et al, 2006). In summary: i) Plasmodium PKs are divergent from their human counterparts, and it is difficult to reconstruct signalling pathways from sequence databases, ii) a collection of parasite clones lacking specific kinases has been constituted and is growing (in both P. berghei and P. falciparum), allowing the study of phenotypes mostly in sexual development/sporogony, iii) some PKs have been demonstrated to be essential for the asexual cycle, and iv) several recombinant PKs are available for biochemical studies and drug discovery activities.…”

Section: Protein Kinases (Pks)mentioning

confidence: 99%

“…The protein kinases CDPK4 and Pbmap-2 have been associated with the production of male gametes (Billker et al, 2004;Khan et al, 2005;Rangarajan et al, 2005), Pbnek-4 and Pbnek-2 with ookinete maturation (Reininger et al, 2005;Reininger et al, 2009), and PbCDPK3 and guanylate cyclise beta with ookinete physiology (Ishino et al, 2006;SidenKiamos et al, 2006;Hirai et al, 2006). The role of signalling molecules in several other phases of sexual differentiation is however completely unknown, despite the fact that some of these processes, such as the establishment of the gametocyte parasitophorous vacuole, or gamete emergence are intrinsically complex cellular rearrangements, which proceed in response to specific cellular and environmental signals.…”

Section: A B Sexual Developmentmentioning

confidence: 99%

Signalling in malaria parasites – The MALSIG consortium

et al. 2009

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Summary :Depending on their developmental stage in the life cycle, malaria parasites develop within or outside host cells, and in extremely diverse contexts such as the vertebrate liver and blood circulation, or the insect midgut and hemocoel. Cellular and molecular mechanisms enabling the parasite to sense and respond to the intra-and the extra-cellular environments are therefore key elements for the proliferation and transmission of Plasmodium, and therefore are, from a public health perspective, strategic targets in the fight against this deadly disease. The MALSIG consortium, which was initiated in February 2009, was designed with the primary objective to integrate research ongoing in Europe and India on i) the properties of Plasmodium signalling molecules, and ii) developmental processes occurring at various points of the parasite life cycle. On one hand, functional studies of individual genes and their products in Plasmodium falciparum (and in the technically more manageable rodent model Plasmodium berghei) are providing information on parasite protein kinases and phosphatases, and of the molecules governing cyclic nucleotide metabolism and calcium signalling. On the other hand, cellular and molecular studies are elucidating key steps of parasite development such as merozoite invasion and egress in blood and liver parasite stages, control of DNA replication in asexual and sexual development, membrane dynamics and trafficking, production of gametocytes in the vertebrate host and further parasite development in the mosquito. This article, which synthetically reviews such signalling molecules

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A calcium‐dependent protein kinase regulates Plasmodium ookinete access to the midgut epithelial cell

Cited by 205 publications

References 28 publications

The development of malaria parasites in the mosquito midgut

The development of malaria parasites in the mosquito midgut

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms inPlasmodium falciparum

Signalling in malaria parasites – The MALSIG consortium

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