Projektbeschreibung
FIKK-Kinasen in Malariaparasiten erforschen
Bei Malaria handelt es sich um eine lebensbedrohliche Infektion. Ihre schwerste Form wird durch den Protozoenparasiten Plasmodium falciparum verursacht. Die wichtigsten Faktoren sind die Zytoadhäsion infizierter roter Blutkörperchen am Wirtsendothel und die Versteifung der infizierten roten Blutkörperchen, die ihre Ausscheidung in der Milz behindert und das Überleben der Parasiten fördert. Der Parasit muss abwägen zwischen der Verhinderung seiner eigenen Beseitigung durch ausreichend starke Zytoadhäsion und Kontrolle der Rigidität und der Tötung des Wirts. Vieles deutet darauf hin, dass der Parasit seine Zytopathieeigenschaften über die FIKK-Kinasen schnell regulieren kann, weshalb es wichtig ist, die Funktion der FIKK zu verstehen. Das EU-finanzierte Projekt VirulenceControl wird fortschrittliche Ansätze anwenden, um die Rolle der FIKK-Kinasen und ihre molekularen Grundlagen bei der Kontrolle von Zytoadhäsion und Rigidität unter Bedingungen zu ermitteln, die häufig im menschlichen Wirt anzutreffen sind.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
ERC - Support for frontier research (ERC)Gastgebende Einrichtung
1067-001 LISBOA
Portugal