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 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.

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

“…T cell epitopes from HGXPRT may be useful alone as an immunogen or may be an ideal component that could be linked to or mixed with other vaccine molecules, all of which are currently designed to stimulate a protective antibody responses (5) or an immune response to protect against disease symptoms per se (26,34). By adding an additional type of immune response, it is likely that the chances of developing a successful vaccine will greatly improve.…”

“…A side effect of the activation of parasite-specific T cells may be immunopathology (15), which might explain why not all vaccinated or T cell-transfused recipients survive, even though the parasite densities are significantly reduced in all mice. A vaccine aimed at inducing cell-mediated immunity may benefit greatly by combination with an antidisease vaccine (26).…”

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

“…Antibodies against Plasmodium falciparum GPI ameliorate some toxic manifestations of murine malaria [93] and can inhibit TNF/ production by mononuclear cells [94]. However, solid evidence for a clinical effect in humans remains lacking [95].…”

Inflammatory cytokine and humoral responses to Plasmodium falciparum glycosylphosphatidylinositols correlates with malaria immunity and pathogenesis

“…In fact, the ability of P. falciparum infected red blood cells to sequester in the deep endothelia of vital organs, including brain, liver, and spleen, leads to the accumulation of high concentrations of toxic parasite components at sites of sequestration, resulting in strong induction of pro‐inflammatory cytokine production, endothelial damage, organ dysfunction, and life threatening pathological conditions. Several studies have shown that glycosylphosphatidylinositols (GPIs) of parasites is one of the parasite toxic factors that contribute to malaria pathogenesis 8, 9, 10, 11, 12, 13. This idea was based on the ability of GPIs to induce production of TNF‐α, IL‐1, IL‐6, and IFN‐γ in macrophages and cause symptoms reminiscent of severe malaria (SM) illnesses, including pyrexia, hypoglycemia, and lethal cachexia in animals 12.…”

“…This idea was based on the ability of GPIs to induce production of TNF‐α, IL‐1, IL‐6, and IFN‐γ in macrophages and cause symptoms reminiscent of severe malaria (SM) illnesses, including pyrexia, hypoglycemia, and lethal cachexia in animals 12. The idea was further substantiated by the fact that immunization with parasite GPIs reduced the inflammation associated with acute Plasmodium berghei infection in mice 13, and that GPIs activate CD36‐, TLR2‐, and TLR4‐dependent signaling cascades to induce inflammatory cytokines and nitric oxide production from human macrophages in vitro 8, 10, 11. However, the relationship between GPI‐induced inflammatory cytokines, such as TNF‐α, IL‐6 and IL‐1, and IgG responses and outcome in SM in human is not well understood.…”