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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045548-02
Application #
6170373
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Gottlieb, Michael
Project Start
1999-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$128,252
Indirect Cost
Name
Walter and Eliza Hall Institute Medical Research
Department
Type
DUNS #
753236256
City
Parkville
State
Country
Australia
Zip Code
VIC, -3052
Hansen, Diana S; D'Ombrain, Marthe C; Schofield, Louis (2007) The role of leukocytes bearing Natural Killer Complex receptors and Killer Immunoglobulin-like Receptors in the immunology of malaria. Curr Opin Immunol 19:416-23
D'Ombrain, Marthe C; Hansen, Diana S; Simpson, Ken M et al. (2007) gammadelta-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-gamma response to Plasmodium falciparum malaria. Eur J Immunol 37:1864-73
Hansen, Diana S; Evans, Krystal J; D'Ombrain, Marthe C et al. (2005) The natural killer complex regulates severe malarial pathogenesis and influences acquired immune responses to Plasmodium berghei ANKA. Infect Immun 73:2288-97
Hansen, Diana S; Siomos, Mary-Anne; Buckingham, Lynn et al. (2003) Regulation of murine cerebral malaria pathogenesis by CD1d-restricted NKT cells and the natural killer complex. Immunity 18:391-402
Hansen, Diana S; Siomos, Mary-Anne; De Koning-Ward, Tania et al. (2003) CD1d-restricted NKT cells contribute to malarial splenomegaly and enhance parasite-specific antibody responses. Eur J Immunol 33:2588-98
Delorenzi, Mauro; Sexton, Adrienne; Shams-Eldin, Hosam et al. (2002) Genes for glycosylphosphatidylinositol toxin biosynthesis in Plasmodium falciparum. Infect Immun 70:4510-22