Erythrocytes, which are incapable of endocytosis, can be infected by the malaria parasite Plasmodium falciparum. How this parasite gets into erythrocytes is a long-standing puzzle. Now, in a study published in Science, Harrison et al. link signalling by host (erythrocyte) proteins to the entry of P. falciparum and other malarial parasites.
In the first step of erythrocyte invasion the malaria parasite is internalised into a vacuole — the parasite vacuole — formed by the erythrocyte membrane. Multiplication of malarial parasites inside erythrocytes, and the release of parasitic waste products, produces the episodic chills and fever that characterize malaria. Previous work from the same laboratory showed that a host heterotrimeric G protein — Gαs, one of three G proteins in erythrocytes — enriched in cholesterol-rich membrane rafts was specifically recruited to the parasite vacuolar membrane. Heterotrimeric G proteins are signal transduction proteins in eukaryotes, which are activated by binding to receptors called G-protein coupled receptors (GPCRs) and transduce extracellular information (such as hormones) to activate cellular proteins. But their function in erythrocytes is poorly understood. Here, Harrison and co-workers show that the erythrocyte GPCR that Gαs interacts with — β-AR — is also recruited to the parasite vacuole.
Specifically blocking activation of Gαs using synthetic peptides matching Gαs sequences that compete for interaction with β-AR led to a dramatic reduction in erythrocyte infection by P. falciparum. Stimulation of GPCRs (to activate Gαs) enhanced parasite infection of erythrocytes. Strikingly, inhibiting activation of Gαs in a mouse model for malaria (Plasmodium berghei) reduced parasite infection. Activating Gαs promotes erythrocyte invasion by malaria, and this mechanism is conserved across malaria species.
The link between host cell signals and regulating establishment of the parasite vacuole is clear. The next big hurdles are finding out how Gαs-coupled receptors are stimulated in the first place and which effector molecules come in to play downstream of Gαs in erythrocytes. The authors speculate that catecholamines produced during infection could switch on Gαs — coupled receptors which in turn signal to rearrange the cytoskeleton and help the parasite to invade the erythrocyte. Whether modification of Gαs regulates other erythrocyte membrane functions — which could relate to diseases like haemolytic anaemias — remains to be seen.
ORIGINAL RESEARCH PAPER
Harrison, T. et al. Erythrocyte G Protein-coupled receptor signaling in malarial infection. Science 301, 1734–1736 (2003).
Haldar, K. et al. Protein and lipid trafficking induced in erythrocytes infected by malaria parasites. Cell Microbiol. 4, 383–395 (2002).
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Jones, S. Inviting malaria in. Nat Rev Microbiol 1, 89 (2003). https://doi.org/10.1038/nrmicro761