Abstract
The motility and invasion of Plasmodium parasites is believed to require a cytoplasmic actin-myosin motor associated with a cell surface ligand belonging to the TRAP (thrombospondin-related anonymous protein) family. Current models of invasion usually invoke the existence of specific receptors for the TRAP-family ligands on the surface of the host cell; however, the identities of these receptors remain largely unknown. Here, we identify the GPI-linked protein Semaphorin-7A (CD108) as an erythrocyte receptor for the P. falciparum merozoite-specific TRAP homolog (MTRAP) by using a systematic screening approach designed to detect extracellular protein interactions. The specificity of the interaction was demonstrated by showing that binding was saturable and by quantifying the equilibrium and kinetic biophysical binding parameters using surface plasmon resonance. We found that two MTRAP monomers interact via their tandem TSR domains with the Sema domains of a Semaphorin-7A homodimer. Known naturally-occurring polymorphisms in Semaphorin-7A did not quantitatively affect MTRAP binding nor did the presence of glycans on the receptor. Attempts to block the interaction during in vitro erythrocyte invasion assays using recombinant proteins and antibodies showed no significant inhibitory effect, suggesting the inaccessibility of the complex to proteinaceous blocking agents. These findings now provide important experimental evidence to support the model that parasite TRAP-family ligands interact with specific host receptors during cellular invasion.
Highlights
Plasmodium falciparum is the etiological agent of the most severe form of malaria causing over one million deaths annually, primarily in African children [1]
Apicomplexan parasites are one of the most significant groups of pathogens infecting humans and include Plasmodium falciparum, the parasite responsible for malaria. These parasites critically depend on their human host and must invade our cells to multiply; understanding this invasion process - with the eventual aim of therapeutically preventing it - has been a focus for scientific investigation
A key component of the invasion machinery is a family of proteins which traverse the membrane surrounding the parasite: the part remaining within the parasite connects to a molecular motor that powers invasion, whilst the surface-exposed region is thought to interact with proteins on the surface of the target host cell
Summary
Plasmodium falciparum is the etiological agent of the most severe form of malaria causing over one million deaths annually, primarily in African children [1]. The parasite lifecycle is complex and involves distinct stages that can recognise and invade differentiated cell types of both the human host and the mosquito vector. These stages are characterised by different invasive properties: ookinetes must cross the epithelial cells of the mosquito gut; sporozoites target both the secretory cells of the mosquito salivary glands and the hepatocytes of the human host, which they can either traverse or invade; and merozoites invade human erythrocytes. The ability of each stage to invade their target cells is an obligatory step in the lifecycle of the parasites and these events have been considered attractive points for therapeutic intervention. The actin filaments are coupled via the glycolytic enzyme aldolase [3,4] to parasite cell surface proteins or ‘‘invasins’’ belonging to the TRAP (thrombospondin-related anonymous protein) family, which in turn are thought to bind via their extracellular region to host cell surface receptors thereby coupling the actin-myosin power-stroke into forwards movement of the parasite (Figure 1 A)
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