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SIGMAL


Malaria

Targeting Malaria Transmission Through Interference with Signalling in Plasmodium falciparum Gametocytogenesis
Framework programme:
6
Call:
2
Project number:
LSHP- CT-2004 -012174
EC contribution:
€ 984,000
Duration:
27 months
Type:
STREP
Starting date:
1 March 2005

Keywords: Malaria; transmission; gametocyte; cell signalling; protein phosphorylation; antimalarial

Summary:

Inhibiting transmission of the malaria parasite from infected humans to the mosquito vector would be of considerable interest in the context of malaria control, especially in order to prevent the dissemination of drug-resistant genotypes. Since only sexual forms of the parasite (the gametocytes) are infective to the mosquito, blocking gametocytogenesis would prevent transmission, but the molecular control of gametocytogenesis is not understood. Our laboratories have independently brought significant contributions to the characterisation of (i) components of signalling pathways, some of which are likely to be involved in differentiation, and (ii) proteins expressed at the onset of gametocytogenesis, such as Pfg27 and Pfs16. It is proposed to merge these lines of investigation to generate an integrated picture of the early events of sexual development at the molecular level. Furthermore, we will develop screening assays for enzymes suspected to be involved in gametocytogenesis, to identify compounds able to interfere with malaria transmission.

Background:

Malaria is a major public health problem in most of the developing world, and the morbidity and mortality burden inflicted by this disease on many developing countries significantly contributes to hinder their socio-economic development. The emergence and spread of malaria parasites that are resistant to existing anti-malarials exacerbates this problem. A way to control the spread of drug-resistant parasites would be to prevent transmission of the parasite from infected humans to the mosquito vector. To infect a mosquito, the parasite must first develop into specialised sexual forms, the male and female gametocytes, while in the bloodstream of the human host. Although proteins that are specifically expressed at the onset of gametocyte formation have been characterised, the molecular mechanisms controlling this phenomenon remain to be elucidated. It is likely that intracellular signalling, and particularly the phosphorylation of proteins, is involved in gametocyte differentiation. Interference with protein kinases (the enzymes responsible for protein phosphorylation) that can be identified as essential for sexual development of the parasite may provide the basis of transmission-blocking drugs.

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