Transmission-blocking interventions eliminate malaria from laboratory populations

Blagborough, Andrew M.; Churcher, Thomas S.; Upton, Leanna M.; Ghani, Azra C.; Gething, Peter W.; Sinden, Robert E.

doi:10.1038/ncomms2840

Cited by 98 publications

(124 citation statements)

References 29 publications

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“…Thus, many predicted sexual stage proteins remain uncharacterized and have unknown functions; specifically, of the 2430 proteins identified by mass-spectrometry in P. falciparum gametocytes (stages I-II, IV and V) [3,4], 830 (34%) are annotated with "unknown function" (www.plasmodb.org; June 5, 2014). Their molecular and cellular descriptions are vital to prioritize candidate surface proteins for transmission-blocking vaccine approaches that interfere with parasite development or inhibit infection of the mosquito vector by the ookinete [5]. Examples of such targets are the P. falciparum zygote and ookinete stage surface proteins Pfs25 and Pfs28 [6,7].…”

Section: Introductionmentioning

confidence: 99%

Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium

Rao

Santos

Pain³

et al. 2016

Parasitology International

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Please cite this article as: Rao Pavitra N., Santos Jorge M., Pain Arnab, Templeton Thomas J., Mair Gunnar R., Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium, Parasitology International (2016), doi: 10.1016/j.parint.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Introductionmentioning

confidence: 99%

Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium

Rao

Santos

Pain³

et al. 2016

Parasitology International

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“…Gametocytes mediate the transmission of the pathogen from the human host to an Anopheles mosquito during blood feeding. As shown in other studies, even a low transmission-blocking activity can have a substantial impact on the reproduction rate of the parasite, and hence on the overall malaria risk and prevalence (72). Whether plasmodione's activity against early gametocytes is sufficient to decrease transmission of the parasite must be addressed further in the future by use of adequate in vivo models.…”

Section: Discussionmentioning

confidence: 99%

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.M alaria remains one of the most severe infectious diseases that disproportionately affects the public health and economic welfare of the world's poorest communities. The causative agents of malaria are protozoan parasites of the genus Plasmodium. Among the five Plasmodium species that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), P. falciparum is the most virulent and is responsible for severe clinical outcomes and most of the deaths associated with malaria. Until the development of an effective vaccine, chemotherapy remains a major frontline strategy for the control and possible future elimination of malaria. The emergence and rapid spread of drug-resistant parasites undermine efforts at reducing the global disease burden and emphasize the need for drugs with novel chemical entities that exploit new molecular targets while overcoming established drug resistance mechanisms. Ideally, such drugs should quickly kill the pathogenic asexual blood stages of P. falciparum and, in addition, be effective against other developmental stages, in particular the sexual stages that transmit the infection from the human to the mosquito host (1, 2).Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in v...

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“…We believe GCS1 best fi ts this criterion because PbGCS1 protein expression levels are quite low in the parasite, and a lack of PbGCS1 protein completely abrogates parasite fertility (Khan et al 2005 ;Hirai et al 2008 ). Recently, Blagborough et al and our group performed experiments demonstrating that an anti-PbGCS1 antibody signifi cantly, but not completely, blocked parasite reproduction based on IVF assays (Blagborough et al 2013 ;Hirai et al unpublished data). This failure to completely inhibit reproduction may arise from PbGCS1 possessing many cysteine residues and displaying a complex conformation that is not recapitulated by the recombinant protein, resulting in less effective antibody production.…”

Section: Application Of Fertilization Factors To Anti-malarial Vaccinmentioning

confidence: 98%

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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Transmission-blocking interventions eliminate malaria from laboratory populations

Cited by 98 publications

References 29 publications

Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium

Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Fertilization Mechanisms of the Rodent Malarial Parasite Plasmodium berghei

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