Neutralization of Malaria GlycosylphosphatidylinositolIn Vitroby Serum IgG from Malaria-Exposed Individuals

Abstract

Parasite-derived glycosylphosphatidylinositol (GPI) is believed to be a major inducer of the pathways leading to pathology and morbidity during Plasmodium falciparum infection and has been termed a malaria "toxin." The generation of neutralizing anti-GPI ("antitoxic") antibodies has therefore been hypothesized to be an important step in the acquisition of antidisease immunity to malaria; however, to date the GPI-neutralizing capacity of antibodies induced during natural Plasmodium falciparum infection has not been evaluated. Here we describe the development of an in vitro macrophage-based assay to assess the neutralizing capacity of malarial GPI-specific IgG. We demonstrate that IgG from Plasmodium falciparum-exposed individuals can significantly inhibit the GPI-induced activation of macrophages in vitro, as shown by reduced levels of tumor necrosis factor production and attenuation of CD40 expression. The GPI-neutralizing capacity of individual IgG samples was directly correlated with the anti-GPI antibody titer. IgG from malaria-exposed individuals also neutralized the macrophage-activating effects of P. falciparum schizont extract (PfSE), but there was only a poor correlation between PfSE-neutralizing activity and the anti-GPI antibody titer, suggesting that PfSE contains other macrophage-activating moieties, in addition to GPI. In conclusion, we have established an in vitro assay to test the toxin-neutralizing activities of antimalarial antibodies and have shown that anti-GPI antibodies from malaria-immune individuals are able to neutralize GPI-induced macrophage activation; however, the clinical relevance of anti-GPI antibodies remains to be proven, given that malarial schizonts contain other proinflammatory moieties, in addition to GPI.

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

“…GPI has been proposed as a putative malaria toxin eliciting the inflammatory response contributing to pathogenesis [12]. On one hand, GPIs initiate the release of proinflammatory cytokines including TNF-a, IL-1, and IL-6, on the other hand antibodies against GPI mediate an inhibition of cytokines release as demonstrated in vitro [34]. However, no correlation was detected in the present work between anti-GPI IgG levels and plasmatic concentrations of proinflammatory cytokines, TNF-a, and IL-6, during the three days survey.…”

Parasite Carbohydrate Vaccines

“…This is still up for debate, since studies that find an association between PfGPI-specific antibody titer and protection from severe malaria (Brasseur et al, 1990 ; Naik et al, 2000 ; Gowda, 2002 ; Keenihan et al, 2003 ; Perraut et al, 2005 ) are balanced by studies that find no such association (de Souza et al, 2002 ; Boutlis et al, 2005 ; Cissoko et al, 2006 ; Gomes et al, 2013 ; Mbengue et al, 2016 ). However, PfGPI-specific antibodies are reported to show relevant action in modulating immune responses by protecting immune cells against severe P. falciparum- induced inflammatory responses in-vitro (Schofield et al, 1993 ; de Souza et al, 2010 ).…”

Glycans in the roles of parasitological diagnosis and host–parasite interplay

“…GPI anchors can activate macrophages and cells of the vascular endothelium through several signalling pathways that result in the production of chemical mediators, such as NO, tumour necrosis factor (TNF α ) and intracellular adhesion molecules I (ICAM-I). This observation led tp exploration of this molecule as a vaccine target (Schofield et al ., 2002), a concept later reinforced by a study that demonstrated that presence of specific antibodies to P. falciparum GPI could neutralize the strong inflammatory response that GPI stimulates (de Souza et al ., 2010).…”