Descripción del proyecto
Un análisis más detallado de las cinasas FIKK en los parásitos del paludismo
El paludismo es una infección que supone un peligro para la vida del paciente. La forma más grave la provoca el parásito protozoo «Plasmodium falciparum». Los principales factores son la citoadhesión de los eritrocitos infectados al endotelio del hospedador, así como la rigidificación de los eritrocitos infectados, que obstruye su eliminación en el bazo y favorece la supervivencia del parásito. El parásito debe encontrar el equilibrio entre impedir su propia eliminación, mediante una citoadhesión y control de la rigidez lo suficientemente fuertes, y matar al hospedador. Existen pruebas contundentes de que el parásito puede regular rápidamente sus propiedades de citopatía a través de las cinasas FIKK, lo cual confiere importancia a la comprensión de la función de las FIKK. El equipo del proyecto VirulenceControl, financiado con fondos europeos, empleará métodos avanzados para identificar el papel de las cinasas FIKK y sus fundamentos moleculares en el control de la citoadhesión y la rigidez en condiciones frecuentes en el hospedador humano.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
1067-001 LISBOA
Portugal