Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria.
The malaria parasite Plasmodium falciparum infects 5-10% of the world's population and kills two million people annually. 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 toxin; 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 NH(2)-CH(2)-CH(2)-PO(4)-(Man alpha 1-2)6Man alpha 1-2Man alpha 1-6Man alpha 1-4GlcNH(2)alpha 1-6myo-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.
Schofield
Louis
L
Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia. schofield@wehi.edu.au
Hewitt
Michael C
MC
Evans
Krystal
K
Siomos
Mary-Anne
MA
Seeberger
Peter H
PH
D000138:Acidosis / Q000150:complications / Q000517:prevention & control; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology; D000992:Antitoxins / Q000276:immunology*; D002240:Carbohydrate Sequence; D004195:Disease Models, Animal; D017261:Glycosylphosphatidylinositols / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology*; D008288:Malaria / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D016779:Malaria, Cerebral / Q000150:complications / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000737:chemistry / Q000276:immunology* / Q000472:pathogenicity*; D011654:Pulmonary Edema / Q000150:complications / Q000517:prevention & control
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D000992:Antitoxins; D017261:Glycosylphosphatidylinositols; D017780:Malaria Vaccines