Descripción del proyecto
Los mecanismos moleculares subyacentes a la resistencia a la artemisinina en la malaria
Durante las fases de desarrollo de la sangre en el protozoo «Plasmodium falciparum», responsable de la malaria, el parásito internaliza gran parte del citosol de la célula hospedadora a través de un proceso endocítico y lo digiere en la vacuola alimentaria. Estudios recientes desvelaron una conexión esencial entre este proceso de endocitosis y la resistencia del parásito al fármaco de primera línea, la artemisinina, e identificaron una serie de proteínas que participan en la endocitosis, incluida Kelch13, el marcador molecular de la resistencia a la artemisinina. El objetivo del proyecto MALART es elucidar los mecanismos moleculares de la endocitosis, en particular investigando la función de Kelch13 en el proceso y los mecanismos compensatorios que utiliza el parásito durante el desarrollo de la resistencia.
Objetivo
Blood stages of the protozoan parasite Plasmodium falciparum are responsible for malaria, a disease that kills more than 400'000 people annually. During its development in red blood cells the parasite internalises a large part of the host cell cytosol (hemoglobin) in an endocytic process and digests it in its food vacuole. We recently identified a critical connection of this hemoglobin endocytosis with resistance of the parasite to the current frontline drug Artemisinin, revealing the mechanism of resistance. Artemisinin is activated by hemoglobin degradation products and we found that Artemisinin resistant parasite endocytose less. Using a toolbox of recently established approaches to carry out functional studies in malaria parasites, we identified an entire series of proteins involved in endocytosis that are involved in resistance to Artemisinin. This included Kelch13, the molecular marker of Artemisinin resistance in field samples. This provides us with a unique opportunity (i) to elucidate how these molecules orchestrate endocytosis, a prominent essential process in these parasites that so far is not understood on a molecular level, (ii) to specifically understand the role of Kelch13 in this process and in resistance, and (iii) to elucidate the reason for the fitness cost that is associated with Artemisinin resistance and the compensatory mechanisms the parasite uses to mitigate them. We expect this research program to not only elucidate so far elusive key aspects of the cell biology of this important parasite, but also to identify critical constraints of Artemisinin resistant parasites and possible ways to circumvent ART resistance.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
20359 Hamburg
Alemania