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ADMALI
MALARIA
Framework programme: 5
Project number:
QLK2-CT-2000-00109
EC contribution: € 1 300 000
Duration: 36 months
Type: RS
Starting date: 1 September 2000
Graphic element Adhesive Interactions in Malaria: New Targets for Intervention
Keywords: Malaria; cytoadhesion; drug design

Summary:

The pathophysiology of malaria is, in the main, associated with the ability of erythrocytes infected with malarial parasites to sequester in the deep vascular bed and cause damage to vital organs. The aim of the project is to investigate the molecular mechanisms underpinning sequestration in an effort to identify targets for the development of drugs that prevent and/or reverse cytoadhesion of infected erythrocytes. The consortium has identified novel adhesive interactions, studied the structure, function and evolution of the parasite genes mediating adhesive phenotypes, and developed the first lead compounds capable of inhibiting adhesive interactions.

Problem:

Malaria remains one of the major infectious diseases worldwide. The disease burden is borne mainly by developing countries where the vast majority of the 300-500 million cases and 1.7-3 million deaths occur, imposing a huge burden on under-resourced health systems and limiting the prospects for economic growth and development. The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has made the discovery and production of new therapeutic interventions a priority.  The morbidity and mortality associated with malaria has been attributed, mainly, to the unique ability of Plasmodium falciparum infected erythrocytes to adhere to small vascular endothelial cells and to uninfected erythrocytes. Adhesion to host cells is essential for parasite survival, as it prevents destruction of the parasitised erythrocytes in the spleen. However, sequestration of parasitised erythrocytes in the deep vascular bed of inner organs, such as the brain, lung and kidney, is a major pathogenic factor in severe malarial disease, resulting in localised hypoxia and inflammatory reactions.

To control the progressive development of the life-threatening complications brought about by adhesive events is a major challenge in the therapy of acute severe malaria. Chemotherapeutics that disrupt and/or prevent sequestration of infected erythrocytes in the deep vascular bed will be of immense clinical value, as such an adjuvant treatment would substantially improve microcirculation, reverse tissue hypoxia, remove the pro-inflammatory stimulus from endothelial cells and bring the parasitised erythrocytes back into circulation where they are more accessible to drug killing.

Aim:

The objective of this research proposal is to develop the technological and scientific base that will permit the rational design of anti-adhesive drugs for the treatment of severe malaria. A prerequisite to the successful development of anti-adhesion drugs for the treatment of severe malaria is detailed knowledge of the molecular basis of adhesion phenomena in malaria, including the role that the host and parasite-encoded factors play in this pathogenic process. Therefore, this consortium incorporates a strong basic research programme aimed at the elucidation of the mechanisms underpinning adhesion of P. falciparum infected erythrocytes to host cells at the molecular level. Information gained will be fed back to the project’s  rational drug design programme.

Expected results:

This project will provide a better understanding of the mechanisms underpinning cytoadhesion of P. falciparum-infected erythrocytes in the microvasculature of inner organs. This information will be used to develop lead compounds that will prevent and/or reverse adhesive interactions of parasitised erythrocytes.

Regarding the mechanisms underpinning cytoadhesion, the consortium has focused on a particular parasite-encoded protein, termed Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is responsible for most, if not all, of the cytoadherence associated with parasitised erythrocytes. PfEMP1 is a variant surface antigen. This protein is encoded by the var gene family, with members predominately located within the subtelomeric domains of P. falciparum chromosomes. Differential expression of var genes can lead to drastic changes of both the antigenic properties and tissue tropism in the human host (for example, placental malaria is induced by a switch from CD36 binding to CSA adhesion of the infected erythrocyte). So far we have conducted the following investigations:

  • studied the role of chromatin structure and modification in var gene switching
  • analysed the nuclear architecture, focusing on factors associated with the interaction between the telomere and the nuclear membrane
  • created parasite mutants that display deletions within the defined subtelomeric var gene variant
  • analysed the effect of var gene mutations on the adhesive properties
  • identified novel host cell receptors involved in the adhesion of parasitised erythrocytes to critical target organs of sequestration
  • screened a large library of various glycans for their ability to disrupt adhesion of parasitised erythrocytes to human endothelial cells, CHO cells expressing defined human endothelial cell surface receptors, and placental cryosections
  • established different technologies to examine the adhesive behaviour of infected erythrocytes, using adhesion under shear flow that mimics more closely the conditions in vivo.

Potential applications:

The results of this project will first of all advance our understanding of host/parasite interactions at the molecular level. This is important, as only a detailed understanding of this process will provide novel opportunities for rational drug development programmes. The development of compounds that inhibit adhesion is done in collaboration with the industrial partner, the 4SC AG seated in Martinsried, Germany. Thus, the potential of this research in terms of pharmaceutical applications is constantly being assessed by the 4SC AG. Any promising lead compound will be pursued further by this company.

Coordinator:

Michael Lanzer
Universitätsklinikum Heidelberg
Hygiene Institut / Abteilung Parasitologie
Im Neuenheimer Feld 324
69120 Heidelberg
Germany
Tel: +49 6221 567845
Fax: +49 6221 564643
E-mail: Michael_Lanzer@med.uni-heidelberg.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Alister CraigLiverpool School of Tropical Medicine
Pembroke Place
UK-L3 5QA Liverpool
United Kingdom
Tel: +44 151 708 9393
Fax: +44 151 708 1702
E-mail: acraig@liv.ac.uk
3Artur ScherfInstitut Pasteur - Department of Immunology
25, rue du Roux
FR-75724 Paris
France
Tel: +33 1 45 68 86 16
Fax: +33 1 45 61 31 85
E-mail: ascherf@pasteur.fr
4Mats WahlgrenMicrobiology and Tumour Centre
Karolinska Institutet
Nobels väg 16
SE-171 77 Stockholm
Sweden
Tel: +46 8 728 7277
Fax: +46 8 310525
E-mail: mats.wahlgren@smi.ki.se
5Percy KnolleZentrum für Molekulare Biologie Heidelberg
Im Neuenheimer Feld 282
DE-69120 Heidelberg
Germany
Tel: +49 6221 546815
Fax: +49 6221 545893
E-mail: P.Knolle@ZMBH.uni-heidelberg.de
6Jürg GysinUniversité de la Méditerranée Aix Marseille II
Unité de Parasitologie Expérimentale
Bd. Jean Moulin, 27
FR-133385 Marseille
France
Tel: +33 4 91 32 46 33
Fax: +33 4 91 32 46 43
E-mail: gysin@medecine.univ-mrs.fr
7Daniel Vitt4SC GmbH
Am Klopferspitz 19
DE-82152 Martinsried
Germany
Tel: +49 89 700 7610
Fax +49 89 700 76329
E-mail: vitt@4sc.com

 
 
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