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.

Aim:

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:

1. to establish a map of protein-protein interactions for molecules expressed at the onset of gametocytogenesis, identified within the consortium by conventional and genome-wide approaches
2. to define the role of phosphorylation of Pfg27, an RNA-binding phosphoprotein essential to sexual development whose structure is solved, integrating biochemical, functional and structural approaches
3. to establish the role that protein kinases and proteins expressed specifically in early gametocytes play in differentiation, using a reverse genetics approach
4. to elucidate the organisation of signalling pathways thought to be involved in gametocytogenesis, such as the cyclic nucleotide and mitogen-activated protein kinase (MAPK) pathways, the central components of which have been characterised in our laboratories
5. to establish biochemical assays for signalling protein kinases, and optimise such assays to medium throughput screening.

Expected results:

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.

Potential applications:

Transmission-blocking drugs in the context of anti-malarial chemotherapy.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Pietro Alano	Istituto Superiore di Sanita Viale Regina Elena 299 IT-00161 Rome Italy	Tel: +39 06 499 02226 Fax: +39 06 493 87143 E-mail: alano@iss.it
3	David A. Baker	Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine Keppel Street UK- WC1E 7HT London United Kingdom	Tel: +44 20 7927 2664 or 2326 Fax: +44 20 7636 8739 E-mail: david.baker@lshtm.ac.uk
4	Amit Sharma	Malaria group International Centre for Genetic Engineering and Biotechnology Aruna Asaf Ali Road New Delhi 110067 India	Tel: +91 11 26711731 Fax: +91 11 26711731 E-mail: asharma@icgeb.res.in
5	Laurent Meijer	CNRS Station Biologique place G. Teissier B.P. 74 FR-29682 Roscoff Cedex France	Tel: +33 2 98 29 23 39 Fax: +33 2 98 29 23 42 E-mail: meijer@sb-roscoff.fr Website: http://www.sb-roscoff.fr/CyCell/
6	Francis Mulaa	University of Nairobi Riverside Drive, Chiromo Campus PO Box 30197 Nairobi Kenya	Tel: +254 20 4442534 Fax: +254 20 4442841 E-mail: Mulaafj@uonbi.ac.ke