ELUCIDATING & DISRUPTING PLASMODIUM ERYTHROCYTE-BINDING LIKE LIGAND INTERACTIONS

摘要

ABSTRACT There is a fundamental gap in understanding of interactions required for erythrocyte invasion by Plasmodium parasites. Our long-term goal is to determine how receptor-ligand interactions during erythrocyte invasion are mediated at the molecular level and how they can be exploited for preventative, therapeutic and diagnostic purposes. The objectives of this application are to understand the molecular basis of receptor recognition by the Erythrocyte-binding like (EBL) family and to establish the mode of inhibition of neutralizing monoclonal antibodies that target this family. The central hypothesis of the application is that the binding domains (DBL domains) of EBL family members possess a conserved fold that dimerizes, creating receptor-binding pockets and channels that are used to recognize a variety of receptors, and that inhibitory antibodies target binding pockets and channels either by preventing their formation or their accessibility The rationale for the proposed research is that once the functional regions of the EBL family members have been determined these can be exploited for vaccine design, novel protein-based therapeutics and/or diagnostics. Thus, the proposed research is relevant to that part of the NIH's mission of developing fundamental knowledge that may reduce the burden of human disease. In addition, the proposed research will advance our understanding of receptor- ligand interactions, ligand-antibody interactions and microbial pathogenesis. Supported by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the receptor binding pockets of the EBL family members; and 2) Determine how neutralizing antibodies bind to DBL domains and inhibit invasion. Under the first aim, structural, in vitro and in vivo studies will be used to comprehensively determine the molecular details of interactions mediated by the EBL family. Under the second aim, structural and interaction mapping studies will reveal epitopes of the EBL family targeted by neutralizing antibodies towards identifying epitopes that have the greatest neutralizing potential. The proposed research is significant because it is expected to advance and expand our understanding of receptor-ligand and ligand-antibody interactions and to provide the knowledge required to develop diagnostics, preventative and therapeutic interventions for malaria.