Abstract

The invasion of host erythrocytes by the parasite Plasmodium falciparum initiates the blood stage of infection responsible for the symptoms of malaria. Invasion involves extracellular protein interactions between host erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. Despite significant research effort, many merozoite surface ligands have no known erythrocyte binding partner, most likely due to the intractable biochemical nature of membrane-tethered receptor proteins and their interactions. The few receptor–ligand pairs that have been described have largely relied on sourcing erythrocytes from patients with rare blood groups, a serendipitous approach that is unsatisfactory for systematically identifying novel receptors. We have recently developed a scalable assay called AVEXIS (for AVidity-based EXtracellular Interaction Screen), designed to circumvent the technical difficulties associated with the identification of extracellular protein interactions, and applied it to identify erythrocyte receptors for orphan P. falciparum merozoite ligands. Using this approach, we have recently identified Basigin (CD147) and Semaphorin-7A (CD108) as receptors for RH5 and MTRAP respectively. In this essay, we review techniques used to identify Plasmodium receptors and discuss how they could beapplied in the future to identify novel receptors both for Plasmodium parasites but also other pathogens.

Highlights

  • Malaria is a devastating infectious disease caused by parasites of the Plasmodium genus, of which Plasmodium falciparum is responsible for approximately one million deaths annually (Murray et al, 2012)

  • We have recently developed a scalable assay called AVEXIS, designed to circumvent the technical difficulties associated with the identification of extracellular protein interactions, and applied it to identify erythrocyte receptors for orphan P. falciparum merozoite ligands

  • Given the global medical importance of malaria and the interest in merozoite surface proteins as vaccine candidates, why have so few interactions been identified between host receptors and P. falciparum merozoite surface proteins? Here, we suggest that the answers are partly due to the technical challenges of working with membraneembedded receptor proteins, the typically weak interaction strengths of extracellular protein : protein interactions and the difficulties of expressing Plasmodium proteins in a functionally active recombinant form

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Summary

Introduction

Malaria is a devastating infectious disease caused by parasites of the Plasmodium genus, of which Plasmodium falciparum is responsible for approximately one million deaths annually (Murray et al, 2012). Invasion involves extracellular protein interactions between host erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. Many merozoite surface ligands have no known erythrocyte binding partner, most likely due to the intractable biochemical nature of membrane-tethered receptor proteins and their interactions.

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