Malaria is still a major health problem in most parts of the world and development of novel drugs or a vaccine is urgently needed. In malaria endemic areas, most children <3-4 years have a risk of developing severe malaria, whereas adults have acquired resistance to clinical disease. Recent studies have identified glycosyiphosphatidylinositol (GPI) anchors of P. falciparum as the toxins involved in malaria pathology. Parasite GPIs exert toxic effects by transducing signals leading to the expression of inflammatory cytokines and cell adhesion molecules, which initiate the process of pathogenesis. Since GPIs are pathogemcity factors the acquired immunity in adults must be related significantly to antibody response against GPIs. We recently found that adults in Western Kenya have high levels of parasite GPI-specific antibodies, whereas susceptible children and people not previously exposed to malaria parasite lack such an antibody response; the anti-GPI antibody response correlated with disease protection. Therefore, understanding of the structures, biologic activity, and immunologic properties of the parasite GPIs is likely to offer strategies for the development of novel therapeutics or a vaccine to prevent infection as well as pathogenesis. In this application we propose to study: (1) Study the levels of naturally elicited anti-GPI antibodies in people from different malaria endemic regions and in defined case control studies. 2) Chemically synthesize active parts of GPIs and total GPI structures. (2) Study the GPIs for inductionof proinflammatory responses in macrophages and in experimental animals, and investigate the antigenicity of GPIs. 3) Assess biological cytokine-inducing property of GPIs in macrophages and in experimental animals and their ability to bind anti-GPI antibodies in sera of immune people. (4) Immunize animals with GPIs to produce anti-GPI polyclonal and monoclonal antibodies. Study anti-sera or purified antibodies for neutralization of cytokine-inducing property of GPIs and investigate the ability of ant-GPI antibodies in providing protection against malaria pathogenesis. 5) Study GPIs for Toll-like receptor-mediated induction of TNF-a in macrophages. 6) Study inhibition of GPI biosynthesis using synthetic GPI intermediates and inhibitors of glycosyltransferases. The long-term objectives are to study the role of parasite GPIs in host interactions, and to exploit GPI structures for the development of anti-malarial drugs and a vaccine.
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