Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria

Abstract

The malaria parasite Plasmodium falciparum infects 5–10% of the world's population and kills two million people annually1. Fatalities are thought to result in part from pathological reactions initiated by a malarial toxin. Glycosylphosphatidylinositol (GPI) originating from the parasite has the properties predicted of a toxin2,3,4,5,6; however, a requirement for toxins in general and GPI in particular in malarial pathogenesis and fatality remains unproven. As anti-toxic vaccines can be highly effective public health tools, we sought to determine whether anti-GPI vaccination could prevent pathology and fatalities in the Plasmodium berghei/rodent model of severe malaria. The P. falciparum GPI glycan of the sequence NH2-CH2-CH2-PO4-(Manα1-2)6Manα1-2Manα1-6Manα1-4GlcNH2α1-6myo-inositol-1,2-cyclic-phosphate was chemically synthesized, conjugated to carriers, and used to immunize mice. Recipients were substantially protected against malarial acidosis, pulmonary oedema, cerebral syndrome and fatality. Anti-GPI antibodies neutralized pro-inflammatory activity by P. falciparum in vitro. Thus, we show that GPI is a significant pro-inflammatory endotoxin of parasitic origin, and that several disease parameters in malarious mice are toxin-dependent. GPI may contribute to pathogenesis and fatalities in humans. Synthetic GPI is therefore a prototype carbohydrate anti-toxic vaccine against malaria.

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Figure 1: Synthesis of glycan (1).
Figure 2: Antibodies raised against synthetic GPI glycan recognize native GPI and neutralize toxin activity in vitro.
Figure 3: Immunization against the synthetic GPI glycan substantially protects against murine cerebral malaria, pulmonary oedema and acidosis.

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Acknowledgements

This work was supported by the UNDP/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases, the National Institutes of Health, the Human Frontiers of Science Program and the National Health and Medical Research Council. M.C.H. acknowledges a biotechnology training grant fellowship from the NIH. L.S. is an International Research Scholar of the Howard Hughes Medical Institute.

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Correspondence to Louis Schofield.

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Schofield, L., Hewitt, M., Evans, K. et al. Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 418, 785–789 (2002). https://doi.org/10.1038/nature00937

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