IMMUNOBIOLOGY OF MALARIA GLYCOSYLPHOSPHATIDYLINOSITOL
Principal Investigator: L Schofield
Abstract: Plasmodium falciparum malaria infects 5 percent of the global population and kills 2.5 million people annually. Fatalities result from an inflammatory cascade initiated by a malarial toxin. We have shown that glycosyl-phosphatidylinositol (GPI) is the major toxin responsible for pathogenesis. Immunization of mice with the detoxified P.falciparum GPI glycan NH-CH2-CH-2-PO4- (Manalpha-1-2)6Manalpha1-2Manalpha1-2Manalpha1-6Manalpha 1- 4GlcNH2 l-6myo-Inositol-l-PO4-glycerol, conjugated to a protein carrier prevented experimental cerebral malaria. Protection was also obtained following passive transfer of monoclonal antibodies to the GPI glycan. The P.falciparum GPI glycan is thus a candidate toxoid vaccine, and anti-GPI mAbs may be useful as prophylactic or therapeutic agents in humans. The experiments outlined in this proposal seek to investigate further the involvement of GPI in malarial pathology, and to elucidate the mechanism of toxin action. The GPI toxin is also profoundly immunosuppressive and we seek to investigate the basis of this phenomenon. Interestingly, GPI is the target of a novel immunological mechanism (the CD1/NK T cell pathway), and we aim to understand further this immunological phenomenon with a view to exploiting anti-GPI immune mechanisms. These areas are central to understanding the host/parasite interaction and the development of effective vaccines to several protozoal pathogens.
Funding Period: 1999-09-01 - 2002-08-31
more information: NIH RePORT
- The natural killer complex regulates severe malarial pathogenesis and influences acquired immune responses to Plasmodium berghei ANKADiana S Hansen
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
Infect Immun 73:2288-97. 2005..To date, NKC-encoded innate system receptors have been shown mainly to regulate viral infections. Our data provide evidence for critical NKC involvement in the broad immunological responses to a protozoan parasite...
- gammadelta-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-gamma response to Plasmodium falciparum malariaDiana S Hansen
Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
Eur J Immunol 37:1864-73. 2007..Applied to longitudinal cohort studies in endemic regions, similar comparative phenotyping should allow assessment of the contribution of diverse cell populations and regulatory receptors to risk of infection and disease...
- The role of leukocytes bearing Natural Killer Complex receptors and Killer Immunoglobulin-like Receptors in the immunology of malariaDiana S Hansen
The Walter and Eliza Hall Institute of Medical Research, 1G, Royal Parade, Parkville 3050, Victoria, Australia
Curr Opin Immunol 19:416-23. 2007..Population-based immunogenetic analyses should allow the identification of NKC and KIR loci controlling innate and adaptive immune responses to malaria and associated with altered risk of infection and disease...