Neutralizing monoclonal antibodies to glycosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of Plasmodium falciparum: prospects for the immunotherapy of severe malaria

Abstract

Tumour necrosis factor-alpha (TNF-alpha) is an endogenous mediator of shock and inflammation. Many of the life-threatening and severe pathologies associated with complicated and cerebral malaria are thought to result from the overproduction of this cytokine in response to agents of parasite origin. The identification and characterization of these agents may therefore provide the molecular basis for a detailed understanding of the disease process. Recently it has been shown that glycosylphosphatidylinositols are a novel class of glycolipid toxin produced by the parasite, which substitute for the endogenous inositolglycan-based signal transduction pathways of the host. Glycosylphosphatidylinositol stimulates high levels of TNF-alpha and interleukin-1 production by macrophages and induces hypoglycaemia through an insulin-mimetic activity, and may therefore contribute to the cerebral syndrome and other malarial pathophysiology. That monoclonal antibodies to parasite-derived glycosylphosphatidylinositol can neutralize the toxic activities of whole parasite extracts is also demonstrated here. These findings suggest a central role for glycosylphosphatidylinositol of parasite origin in the aetiology of severe malaria and suggest novel approaches for the immunotherapy or immunoprophylaxis of disease.