Lay summary
Adherence of infected red blood cells to blood capillaries are responsible for the majority of the observed pathology in malaria. This is mediated by a parasite protein on the surface of the infected cell, called PfEMP1. PfEMP1 is variable and encoded by a large number of genes in a given population. In this project we will study the diversity of expressed genes coding for PfEMP1 (var genes) to test our hypothesis that only a limited number of these genes are responsible for pathology. We will extent our studies to sequence larger fragments of the molecule which until now was elusive due to its size. Using a targeting cloning and sequencing strategy, we plan to specifically sequence only var genes but from a large number of patients.We will use this sequence information to select synthetic peptides using an bioinformatics approach to test their immunological recognition and binding capacity to selected molecules.Finally, we will study the fate of PfEMP1 from the parasite’s cytosol through the parasitophorous vacuole into the red blood cell membrane. In this subproject we are interested in potential interaction partners enabling the parasite to modify the host cell to such extend.We hope that the information gained during this project will identify potential virulence factors (selected PfEMP1 molecules) with the option to use these as vaccine candidates. Furthermore, by studying the transport and trafficking of this clinically important molecule through the cell we hope to identify structures and transporters which might become targets for interventions. Understanding the limits of diversity and understanding the molecular events which are necessary to transport PfEMP1 to the surface is of utmost importance. Because PfEMP1 is essential for parasite survival in vivo, understanding this process in detail may open completely new strategies for intervening with this devastating disease.