Role of GPIs in cell signaling and host immune response

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Except for their role in membrane insertion of surface proteins in T. gondii, the biological junctions of GPIs are presently unknown. In other eukaryotic systems, GPIs can display functions involved in signal transduction. One possible function of the GPI anchor might be to allow a closer association of the proteins with themselves and other surface proteins in the membrane (Tomavo, 1996). Consistent with this idea, genetically engineered transmembrane-anchored SAG1 does not show the usual observed association of GPI-anchored SAG1 with itself and/or other proteins (Seeber et al., 1998).

As stated, Toxoplasma free-GPIs elucidate strong and early immunogenic responses during host infection. Data from other protozoa suggest that other functions of GPIs in host immune response are possible. In Plasmodium falciparum, the GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin-1 production by macrophages, and regulates metabolism in adipocytes (Schofield and Hackett, 1993). Deacylation with specific phospholipases abolishes cytokine induction. When administered to mice in vivo the malaria parasite GPI induces cytokine release, a transient pyrexia and hypo-glycemia, and profound and lethal cachexia, in the presence of sensitizing agents. The data suggest that the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process. It has been further demonstrated that Plasmodium GPI directly and specifically increases cell adhesion molecule expression in HUVECs, and parasite cytoadherence (Schofield et al., 1996). These parasites' GPIs induce rapid activation of a tyrosine kinase in macrophages.

The minimal structure requirement for tyrosine kinase activation is the evolutionarily conserved core glycan sequence Mana1,2Mana1,6Mana1-4GlcN1-6myo-inositol. The GPI alone appears sufficient to mimic the activities of malaria parasite extracts in the signaling pathway leading to TNF expression (Tachado et al., 1997).

Thus, GPIs of intraerythrocytic Plasmodium falciparum induce pro-inflammatory cytokine responses. It was also reported that adults who have resistance to clinical malaria contain high levels of pertinent anti-GPI antibodies, whereas susceptible children lack or have low levels of short-lived antibody response. Individuals who were not exposed to P. falciparum completely lack anti-GPI antibodies. Absence of a pertinent anti-GPI antibody response correlated with malaria-specific anemia and fever, suggesting that anti-GPI antibodies provide protection against clinical malaria (Naik et al., 2000). These results could be evaluated in studies aimed at the defining the activity of chemically defined structures for toxic-ity, and results would have implications for the development of GPI-based therapies or vaccines.

The P. falciparum GPI glycan consisting of the sequence NH2-CH2-CH2-PO4-(Mana1-2) 6Mana1-2Mana1-6Mana-4GlcNH(2)a1-6myo-inositol-1, 2-cyclic-phosphate was chemically synthesized, conjugated to carriers, and used to immunize mice infected with P. berghei, a rodent model of severe malaria. The recipients were substantially protected against malarial acidosis, pulmonary edema, cerebral syndrome, and fatality (Schofield et al., 2002). Altogether, the above data suggest that GPI is a significant pro-inflammatory endo-toxin of parasitic origin and it may contribute to pathogenesis and fatalities in humans. In addition, GPI may also be used as a prototype carbohydrate anti-toxin vaccine against malaria. It remains to be seen whether GPI has a similar role in clinical toxoplasmosis.

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