Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes.

Wai-Hong Tham,Sash Lopaticki,Christian Doerig,Nicholas T Y Lim,Paul R Gilson,Megan Bird,Brendan S Crabb,Isabelle Lucet,Alan F Cowman,Dominique Dorin-Semblat,Brendan R E Ansell,Greta E Weiss

doi:10.1371/journal.ppat.1005343

Abstract

The most severe form of malaria in humans is caused by the protozoan parasite Plasmodium falciparum. The invasive form of malaria parasites is termed a merozoite and it employs an array of parasite proteins that bind to the host cell to mediate invasion. In Plasmodium falciparum, the erythrocyte binding-like (EBL) and reticulocyte binding-like (Rh) protein families are responsible for binding to specific erythrocyte receptors for invasion and mediating signalling events that initiate active entry of the malaria parasite. Here we have addressed the role of the cytoplasmic tails of these proteins in activating merozoite invasion after receptor engagement. We show that the cytoplasmic domains of these type 1 membrane proteins are phosphorylated in vitro. Depletion of PfCK2, a kinase implicated to phosphorylate these cytoplasmic tails, blocks P. falciparum invasion of red blood cells. We identify the crucial residues within the PfRh4 cytoplasmic domain that are required for successful parasite invasion. Live cell imaging of merozoites from these transgenic mutants show they attach but do not penetrate erythrocytes implying the PfRh4 cytoplasmic tail conveys signals important for the successful completion of the invasion process.

Highlights

The most lethal form of malaria in humans is caused by Plasmodium falciparum
Members of the erythrocyte binding-like (EBL) and reticulocyte binding-like (Rh) protein families, which are present at the apical tip of merozoites as single-pass transmembrane proteins, mediate recognition of red blood cells
Apical organelles in the parasite called rhoptries secrete their proteins and lipid contents to establish the nascent parasitophorous vacuole membrane that surrounds the newly invaded malaria parasite and provides the space into which the invading parasite can move [4].Once the merozoite is inside the red blood cell, the erythrocyte membrane is sealed behind it completing invasion

Summary

Introduction

The merozoite form of this parasite invades red blood cells beginning with initial recognition and attachment to erythrocytes This interaction is dynamic and involves considerable deformation of the erythrocyte membrane as the parasite rolls across the host cell surface [2]. The merozoite reorientates such that its apical prominence is closely juxtaposed with the erythrocyte surface. This allows erythrocyte-binding ligands ( known as adhesins) of the parasite to interact with specific erythrocyte receptors mediating irreversible attachment and commitment to invasion. The invasion process is accomplished within a few minutes [2]

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