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.
Author contributions MGDB, PCD and RK conceived and designed the study. MGDB, JFRC, HSP, JH, RR, OLB, MJB, LCP, AN, HC collected the samples and metadata. AB acquired LC-MS data. LIM led LC-MS data analysis. CC led taxonomy and metadata analysis. QZ led DNA data and multi-omics analysis. JJM performed qPCR. SJS, ME, HC, AN, AB, JJM provided additional contributions to data analysis. LIM
We have investigated intragenic recombination in Block 2 of the merozoite surface protein-1 (MSP-1), where three allele-specific families: K1, Mad20, and RO33 were previously known. Using parasites from western Kenya, we have found a fourth Block 2 allele type, which is a recombinant between Mad20 and RO33 alleles. These recombinant alleles, which we have termed MR, contain sequence from the 5' region of Mad20 and the 3' region of RO33. The results of this study provide new data on the complexity of the MSP-1 antigen gene, which is a candidate vaccine antigen, and further support the importance of intragenic recombination in generating genetic variability in Plasmodium falciparum parasites in nature.
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