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A Simple Protocol for Platelet-mediated Clumping of Plasmodium falciparum-infected Erythrocytes in a Resource Poor Setting
Published on: May 16, 2013
Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites
Michelle J Boyle1, Jack S Richards, Paul R Gilson
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Abstract:
During erythrocyte invasion, Plasmodium falciparum merozoites use multiple receptor-ligand interactions in a series of coordinated events, but current knowledge of these interactions is limited. Using real-time imaging of invasion, we established that heparin-like molecules block early, and essential, events in erythrocyte invasion by merozoites. All P falciparum isolates tested, and parasites using different invasion pathways were inhibited to comparable levels. Furthermore, it was not possible to select for heparin-resistant parasites. Heparin-like molecules occur naturally on the surface of human erythrocytes, where they may act as receptors for binding of merozoite surface proteins. Consistent with this, we demonstrated that MSP1-42, a processed form of merozoite surface protein 1 (MSP1) involved in invasion, bound heparin in a specific manner; furthermore, binding was observed with the secondary processing fragment MSP1-33, but not MSP1-19. We defined key structural requirements of heparin-like molecules for invasion inhibition and interactions with MSP1-42. Optimal activity required a degree of sulfation more than or equal to 2, disulfation of the N-acetylglucosamine or hexuronic acid residue, and a minimum chain length of 6 monosaccharides. These findings have significant implications for understanding P falciparum invasion of erythrocytes and the development of novel therapeutics and vaccines.
Insights
Heparin-like molecules on red blood cells block Plasmodium falciparum invasion by binding merozoite surface protein 1 (MSP1). This interaction is crucial for blocking malaria parasite entry and offers new therapeutic targets.
Area of Science:
- Malariology
- Parasitology
- Molecular Biology
Background:
- Plasmodium falciparum merozoites employ complex receptor-ligand interactions for erythrocyte invasion.
- The precise mechanisms and molecular players in these interactions remain incompletely understood.
Purpose of the Study:
- To investigate the role of heparin-like molecules in Plasmodium falciparum erythrocyte invasion.
- To identify specific merozoite surface proteins that interact with heparin-like molecules.
Main Methods:
- Real-time imaging of Plasmodium falciparum invasion into erythrocytes.
- Inhibition assays using heparin-like molecules.
- Biochemical assays to study protein-ligand interactions, including binding studies with merozoite surface protein 1 (MSP1) fragments and heparin.
Main Results:
- Heparin-like molecules significantly inhibit early erythrocyte invasion by Plasmodium falciparum merozoites, irrespective of parasite isolate or invasion pathway.
- Parasite resistance to heparin was not observed.
- Merozoite surface protein 1 (MSP1) processing fragment MSP1-42 specifically binds to heparin, with binding also observed for MSP1-33 but not MSP1-19.
- Optimal inhibition and binding required specific structural features of heparin-like molecules, including sulfation degree, disulfation, and chain length.
Conclusions:
- Heparin-like molecules on erythrocytes are critical for blocking Plasmodium falciparum invasion.
- Merozoite surface protein 1 (MSP1) interaction with these molecules is a key event in the invasion process.
- These findings provide insights into malaria parasite invasion and suggest novel therapeutic and vaccine targets.
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