Wednesday, February 5, 2025
2/5/2025
DESCRIPTION (provided by the applicant): The etiological agent responsible for the severe form of malaria in humans is the intraerythrocytic protozoan parasite Plasmodium falciparum. Clinical manifestations of P. falciparum malaria include cerebral malaria, a major cause of death from this disease, where infected erythrocytes sequester in the deep vascular beds of the brain. During growth of the asexual stage of the parasite in human erythrocytes, extensive changes occur in the structural and functional properties of the infected erythrocyte, including the development of knob structures and the ability to adhere to endothelium. Crucial to these changes are proteins of parasite origin that are either deposited on the inner aspect of the erythrocyte membrane or inserted into it. Several parasite proteins are present at the cytoplasmic side of the knob structure including the krab-associated histidine rich protein and PfEMP3. The adhesive properties of P. falciparum infected erythrocytes are due to the antigenically variant protein PfEMPI that is concentrated in the knob on the outside of the membrane. Transport of proteins to the erythrocyte cytoskeleton and surface is a multi-step process involving trafficking across the parasite membrane, parasitophorous vacuole membrane and into the REIC cytoplasm where they can associate with membranous structures know as Maurer's clefts and from there reach their final destination. An understanding of this trafficking process is an important biological question but significantly will provide the basis for novel experimental approaches to identify and elucidate the role of exported proteins in the adhesive and mechanical properties of P. falciparum-infected erythrocytes. We hypothesize that interaction of these proteins with Maurer's clefts and subsequent trafficking steps are essential for correct localization and function involving defined targeting motifs and protein-protein interactions, To test these hypotheses, we will make P.falciparum transfectants lacking expression of defined proteins, express mutant forms or chimeric proteins that can be analyzed. We will use this information to define a core subset of proteins exported to the erythrocyte by the parasite responsible for remodeling of the erythrocyte. Functional analysis of these proteins will increase our understanding of the role of proteins in the regulation of cell structure and the mechanical and adhesive properties. These studies will contribute to and increased understanding of the pathophysiology of falciparum malaria.
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