Description du projet
Un examen plus approfondi des kinases FIKK dans les parasites du paludisme
Le paludisme est une infection potentiellement mortelle. Sa forme la plus grave est causée par le parasite protozoaire Plasmodium falciparum. Les principaux facteurs de la maladie sont la cytoadhésion des globules rouges infectés (iRBC) à l’endothélium de l’hôte et la rigidification de ces iRBC, qui entrave leur élimination dans la rate et favorise la survie du parasite. Le parasite doit donc trouver un équilibre entre la prévention de sa propre élimination par une cytoadhésion suffisamment forte et le contrôle de la rigidité et la mort de l’hôte. Des données convaincantes indiquent qu’il est capable de rapidement réguler ses propriétés cytopathiques par l’intermédiaire des kinases FIKK, d’où l’importance de mieux comprendre leur fonction. Le projet VirulenceControl, financé par l’UE, appliquera des approches avancées pour identifier le rôle des kinases FIKK et leurs fondements moléculaires dans le contrôle de la cytoadhésion et de la rigidité dans des conditions fréquemment rencontrées chez l’hôte humain.
Objectif
The most severe form of malaria in humans is caused by Plasmodium falciparum. Cytoadhesion of infected red blood cells (iRBCs) to host endothelium and iRBC rigidification are the major contributors to pathology. Cytoadhesion is mediated by transport of a protein called PfEMP1 onto the surface of the iRBC. It prevents clearance of iRBCs in the spleen and promotes parasite survival, but can cause the obstruction of blood vessels leading to pathology. Thus, the parasite has to strike a fine balance between preventing its own clearance through sufficiently strong cytoadhesion and control of rigidity, and killing the host. The paradigm in the field is that the strength of cytoadhesion is dominated by expression of PfEMP1 variants with different affinities for host cell receptors. We now have strong evidence that the parasite can rapidly regulate its cytoadhesive properties using a family of atypical kinases (the FIKK kinases) it exports into the host cell. This gives the parasite a yet unrecognized ability to respond to conditions encountered in the host, such as fever or hypoxia in areas of high parasite sequestration, and influence disease outcome. This is important: Of the 6 human infecting Plasmodium species only P. falciparum exports FIKK kinases into the host cell. As this species is responsible for ~95% of all fatal human malaria cases, it is paramount to understand FIKK- function in pathogenesis. We will use cutting edge approaches to: (1) identify the function of FIKK kinases in controlling cytoadhesion and rigidity in conditions frequently encountered in the human host and determine RBC remodelling in samples from patients. (2) Identify the molecular underpinnings of FIKK function in controlling cytoadhesion and (3) perform a thorough biochemical characterisation of the atypical FIKK kinase family. In summary we aim to answer the paramount question about the functional role and the evolution of the FIKK kinases and the pathogenesis of P. falciparum malaria.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
1067-001 LISBOA
Portugal