Keywords: Malaria; transmission; gametocyte; cell signalling; protein phosphorylation; antimalarial
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.
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.
The aims of the project are (i) to further the understanding of gametocyte formation, in particular by characterising the signaling pathways involved, and (ii) to identify inhibitors of protein kinases that may inhibit gametocyte formation.
Specific objectives are:
Improved knowledge of the basic biology of malaria parasites
Determination of novel molecular targets for transmission-blocking intervention
Identification of protein kinase inhibitors able to prevent gametocytogenesis.
Transmission-blocking drugs in the context of anti-malarial chemotherapy.
Wellcome Centre for Molecular Parasitology
University of Glasgow
56 Dumbarton Road
G11 6NU Glasgow
Tel: +44 141 339 8855 x6201
Fax: +44 141 330 5422
|Official Address||Other Information|
|2||Pietro Alano||Istituto Superiore di Sanita|
Viale Regina Elena 299
|Tel: +39 06 499 02226 |
Fax: +39 06 493 87143
|3||David A. Baker||Department of Infectious and |
London School of Hygiene and
UK- WC1E 7HT London
|Tel: +44 20 7927 2664 or 2326|
Fax: +44 20 7636 8739
|4||Amit Sharma||Malaria group |
International Centre for Genetic Engineering
Aruna Asaf Ali Road
New Delhi 110067
|Tel: +91 11 26711731 |
Fax: +91 11 26711731
|5||Laurent Meijer||CNRS |
place G. Teissier
FR-29682 Roscoff Cedex
|Tel: +33 2 98 29 23 39 |
Fax: +33 2 98 29 23 42
|6||Francis Mulaa||University of Nairobi |
Riverside Drive, Chiromo Campus
PO Box 30197
|Tel: +254 20 4442534 |
Fax: +254 20 4442841