Rationale for malaria anti-toxin therapy

Abstract

Glycosylphosphatidylinositols (GPIs) are a distinct class of glycolipids that are present ubiquitously in eukaryotic cells, where they perform a variety of biological processes. GPIs are particularly abundant in protozoa, where they are found as free lipids and attached to proteins. For the asexual blood stages of Plasmodium falciparum, several functionally important parasite proteins, including merozoite surface protein 1 (MSP1), are anchored to the erythrocyte membrane through GPI moieties. Because the enzyme specificity of Plasmodium GPI biosynthesis differs significantly from that of the mammalian host, it has been speculated that parasite GPIs might provide novel targets for antimalarial drugs or vaccines.The pathology of malaria infection has long been considered to be the result of the release of toxins of parasite origin. Tumour necrosis factor-α (TNF- α), which is induced by such malarial toxins, was subsequently identified as a major host mediator of disease. Consequently, its production and that of other pyrogenic cytokines is commonly regarded as a surrogate marker for the initiation of malaria pathological processes. The GPI of P. falciparum has emerged only recently as a candidate toxin, based on its ability to elicit proinflammatory cytokines from macrophages and endothelial cells by activating NFκB transcription factors and on its ability to cause clinical effects in experimental animals that are akin to acute malaria infection (e.g. fever, hypoglycaemia, dyserythropoiesis and vascular damage in the brain). As P. falciparum-infected erythrocytes are sequestered in specific organs, localized elevated toxic responses to the parasite's GPIs can disturb vital physiological functions and cause severe illness and, in the event of cerebral pathology, even death. Antagonists of GPI-mediated signalling and a monoclonal antibody against P. falciparum GPIs can each block the induction of toxicity in vitro, indicating the feasibility of GPI-based immunotherapy.Naik et al.1xGlycosylphosphatidylinositol anchors of Plasmodium falciparum: molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis. Naik, R.S et al. J. Exp. Med. 2000; 192: 1563–1575Crossref | PubMed | Scopus (161)See all References1 postulate, because P. falciparum GPIs are pathogenicity factors, that semi-immune adults living in regions of malaria endemicity should possess GPI-specific protective immunity. This hypothesis was tested by analysing the anti-GPI antibody response in sera from a large cohort of individuals from western Kenya. Their findings demonstrate for the first time that people in malaria-endemic regions elicit a potent GPI-specific immunoglobulin (Ig) G response, and that this increases in an age-dependent (and possibly exposure-dependent) manner. Thus, although adults and older children have high antibody titres, children susceptible to acute P. falciparum infection either have low levels of short-lived antibodies or none at all. Absence of a persistent anti-GPI antibody response was associated with malaria-specific anaemia and fever. Naik et al.1xGlycosylphosphatidylinositol anchors of Plasmodium falciparum: molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis. Naik, R.S et al. J. Exp. Med. 2000; 192: 1563–1575Crossref | PubMed | Scopus (161)See all References1 speculate that antibodies to P. falciparum GPIs are involved in protection against clinical infection. This speculation is based on the discovery of a direct correlation between serum anti-GPI IgG and resistance to malaria pathogenesis; a causal link now needs to be established in a suitable experimental model, between the possession of antibodies to parasite GPIs and prevention of pathogenesis. Understanding the factors associated with resistance to clinical infection, so-called anti-disease immunity, might lead to alternative approaches for malaria control. In this regard, GPIs appear to offer a genuine opportunity.