Framework programme:

6

Call:

3

Project number:

LSHP-CT-2006-037749

EC contribution:

€ 998,327

Duration:

24 months

Type:

STREP

Starting date:

1 October 2006

Keywords: Microparticles, endothelium, cerebral malaria, inflammation, immune activation, membrane vesiculation

Summary:

Cerebral malaria (CM) remains a major public health problem worldwide. The main reason for this is our insufficient knowledge on the mechanisms leading to this complication. The partners of this consortium recently showed that the production of microparticles (MP) is dramatically elevated in patients with CM. Evidence in a murine model indicates that MP may be a pivotal element in CM pathogenesis, and in vitro data on human brain microvascular endothelial cells suggest that reducing MP production by anti-inflammatory drugs correlates with a reduced cytoadherence of parasitised erythrocytes. This projects aims to unravel the mechanisms of MP production, delineate pharmacological ways to interfere with it, and to define the pathophysiological consequences of excessive MP production. It is expected that molecules relevant to the pathogenesis of this disease will be identified through broad spectrum of technologies including astrocytes and endothelial cell culture, flow cytometry, immunohistochemistry and membrane biology among others. This consortium brings together clinical and research teams working in complementary fields and developing specific approaches to tackle the questions being raised. Colleagues coming from countries which experience this endemic problem (including Malawi, Cameroon, Tanzania and India) play a major role in the project. Improving the understanding of CM pathogenesis should open new therapeutic avenues and in the long-term reduce malariaassociated mortality and morbidity by avoiding uncomplicated malaria to evolve in CM.

Background:

Malaria remains a major problem of public health in over one hundred countries worldwide. Close to 500 million people are infected annually with Plasmodium falciparum. The major complications, cerebral malaria (CM) and severe malarial anaemia (SMA), account for more than 2 million deaths annually, essentially in children less than 5 years of age, pregnant women and non-immune individuals. Although numerous metabolic, pathological and physiological abnormalities have been demonstrated to occur in CM, neither the mechanism of coma nor the cause/s of death have been adequately explained. The projects overall aim is to better understand the reasons why uncomplicated malaria (UM) can evolve in about 1% of the cases (ca. 3 million people), into the potentially lethal neurological syndrome of CM; and why established CM even with the best available treatment – ends in death in 15-30% of cases and leaves neurological sequelae in 10% of those who recover. Our rationale is that, once this is understood, new avenues for prevention and/or therapy will be opened up, and new targets for drug design can be investigated.

Aim:

To unravel the mechanisms of MP production and action, define the pathophysiological consequences of excessive MP production and delineate pharmacological ways to interfere with these mechanisms.

To this end, the specific objectives are:

1. To further characterise the phenotype of MP in patients with CM as opposed to those with UM or SMA, and to compare MP phenotypes among different clinical subsets of paediatric CM, and also in CM in adults, a syndrome commonly found in areas of seasonal transmission such as India (Partner 4 and colleagues at NCCS, India)
2. To dissect the mechanisms of MP production
3. To unravel the mechanisms of action of MP and their effects on immune cells
4. To decipher the pathological consequences of MP produced during CM by studying the effects of interactions between MP and various cell types
5. By inferring from the unravelled mechanisms the identity of targets for therapeutic intervention, to act on MP release
6. To find and develop efficient tools able to modulate MP so as to prevent pathology.

The host response to malaria parasites has been divided into two phases, named initiation’ and effector’ phases, respectively. The former pertains to early events of recognition of the pathogen by cells such as NKT, CD4+ and gamma-delta T cells, while the latter involves the events that lead to endothelial cell damage, the endpoint of pathogenic cascade.

Expected results:

This project, in focusing specifically on preventing UM from becoming CM, represents a sustainable solution for developing countries. Indeed, the existing costly tools to protect against the vectors are not 100% efficient, the time scale to intervene is too high, and the problem of drug resistance remains of paramount importance. In several countries some drugs cannot be used anymore due to 100% resistance of the parasites to these once active molecules. Expected results are likely to be of help in the prevention of progression towards severe cases and thereby may help to lower treatment costs estimated according to the WHO for as much as 40% of the public expenditure health in the most affected countries and more than $12 billion in Africa. This project aims to prevent UM from progressing into CM, and should help in reducing malaria-associated mortality and morbidity.

Further, the elucidation of the mechanisms involved in the generation of MP that is related to CM may also lead to new therapeutic approaches in chronic inflammatory diseases such as multiple sclerosis and rheumatoid arthritis in which similar mechanisms might be involved will lead to new insights into pathologies that are not their usual research focus.

Potential applications:

Coordinator:

Giovana CHIMINI
CIML (Centre d'Immunologie de Marseille-Luminy)
Université de la Méditerranée, (CNRS (UMR 6102) and INSERM (U136))
Parc Scientifique et Technologique de Luminy - Case 906
13009 Marseille
France
Tel: +33 (4) 91 26 94 04
Fax: + 33 (4) 91 26 94 30
E-mail: chimini@ciml.univ-mrs.fr
europe@univmed.fr
Website: www.univmed.fr
www.ciml.univ-mrs.fr

Partners: