Glycosylphosphatidylinositol Anchors ofPlasmodium falciparum

Abstract

Induction of proinflammatory cytokine responses by glycosylphosphatidylinositols (GPIs) of intraerythrocytic Plasmodium falciparum is believed to contribute to malaria pathogenesis. In this study, we purified the GPIs of P. falciparum to homogeneity and determined their structures by biochemical degradations and mass spectrometry. The parasite GPIs differ from those of the host in that they contain palmitic (major) and myristic (minor) acids at C-2 of inositol, predominantly C18:0 and C18:1 at sn-1 and sn -2, respectively, and do not contain additional phosphoethanolamine substitution in their core glycan structures. The purified parasite GPIs can induce tumor necrosis factor ␣ release from macrophages. We also report a new finding that adults who have resistance to clinical malaria contain high levels of persistent anti-GPI antibodies, whereas susceptible children lack or have low levels of short-lived antibody response. Individuals who were not exposed to the malaria parasite completely lack anti-GPI antibodies. Absence of a persistent anti-GPI antibody response correlated with malaria-specific anemia and fever, suggesting that anti-GPI antibodies provide protection against clinical malaria. The antibodies are mainly directed against the acylated phosphoinositol portion of GPIs. These results are likely to be valuable in studies aimed at the evaluation of chemically defined structures for toxicity versus immunogenicity with implications for the development of GPI-based therapies or vaccines.

Inflammatory cytokine and humoral responses to Plasmodium falciparum glycosylphosphatidylinositols correlates with malaria immunity and pathogenesis

“…People living in endemic areas have anti‐GPI antibodies 8, 20, 24, which might provide some degree of protection against malaria symptoms. High levels of the anti‐GPI antibodies have been correlated with resistance to clinical symptoms, such as anemia and fever 19, and hence these antibodies were suggested to be an important factor in the protective immunity to malaria 8, 11. Consistent with these results, lower levels of anti‐GPI were observed among Senegalese adults with cerebral malaria compared to individuals with uncomplicated malaria 14.…”

“…P. falciparum GPIs were isolated from the late trophozoite and schizont stages of cultured P. falciparum (FCR3 strain), and purified by HPLC as described earlier 19, 20.…”

The Role of Inositol Acylation and Inositol Deacylation in the Toxoplasma gondii Glycosylphosphatidylinositol Biosynthetic Pathway

“…The presence of sn-2 C18:1 fatty acid on the immunogenic GPI anchors of T. gondii shown here draws obvious parallels to the highly immunogenic T. cruzi trypomastigote GPI anchors, which contain C16:0 (37%), C18:1 (31%), and C18:2 (21%) at the sn-2 position of their alkylacylglycero-lipid component (56), and P. falciparum GPI anchors containing C18:1 (88%) and C18:2 (12%) at the sn-2 position of their diacylglycero-lipid component (47).…”

Plasmodium falciparumGlycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages Is Mediated without Membrane Insertion or Endocytosis

“…Recently we established, by mass spectrometry, the structures of GPIs purified from intraerythrocytic P. falciparum (16). Here, we studied the specific structural elements and nature of interaction involved and the mechanism of cell signaling in GPI-induced TNF-␣ secretion.…”