The intestinal protozoan parasite Entamoeba histolytica is capable of invading and destroying human tissues, leading to potentially life-threatening diseases such as hemorrhagic colitis and extraintestinal abscesses. It is estimated that E. histolytica is responsible for about 50,000,000 cases of invasive amebiasis annually, resulting in 100,000 deaths, and thus rates among the leading parasitic causes of death, surpassed only by malaria and schistosomiasis (1). Morbidity and mortality associated with amebic infection have persisted despite the availability of effective therapy, suggesting that interventions designed to reduce or eliminate disease are needed. In principle, these objectives could be achieved by the introduction of a suitable vaccine. Since humans are the only relevant host for E. histolytica, an effective vaccination program could potentially eradicate amebiasis.
One of the leading candidates for a vaccine to prevent amebiasis is the galactose- and N-acetylgalactosamine-inhibitable lectin. The structure and function of this ameba surface receptor has been studied in considerable detail (for review see references 2 and 3). It is a membrane-associated glycoprotein with disulfide-linked subunits of a molecular mass of 170 and 35 kD, respectively (4). Both subunits of the receptor have been cloned, and their primary structures were deduced from cDNA and genomic sequences (5-8). The galactose- and N-acetylgalactosamine-inhibitable lectin appears to play a key role in amebic pathogenesis. It mediates adherence to colonic mucins (which may be important in intestinal colonization) and mediates binding to host cells (2, 9, 10). Adherence to host cells is critically important in the pathogenesis of intestinal disease and amebic liver abscess, since the killing of cells by amebae is contact dependent (3). Consistent with its role in mediating adherence to target cells, antibodies to certain epitopes on the galactose- and N-acetylgalactosamine lectin can inhibit amebic adherence to target cells. However, it has also been found that antibodies to other epitopes of the lectin can enhance binding of ameba trophozoites to mammalian cells (11). In addition, epitopes of the lectin have been implicated in cell-mediated immune responses to amebae (12), and evidence exist that the ability of E. histolytica to resist complement lysis is mediated by a CD59-like domain of the ameba lectin (13).
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The purified native galactose- and N-acetylgalactosamine- binding lectin has been used to vaccinate gerbils to protect them against amebic liver abscess (14). Although vaccination was protective in most animals, in others there was evidence for a significant increase in liver abscess size, suggesting that the immune response to the lectin could also exacerbate disease. Because of the vaccine potential of this molecule and its many putative functions, we were interested in identifying protective and exacerbative epitopes of the lectin, and in determining whether protective or exacerbative epitopes could be correlated with functional regions of the molecule. Here we have used four nonoverlapping recombinant proteins spanning the sequence of the extracellular region of the heavy chain subunit of the galactose-and N-acetylgalactosamine-inhibitable lectin to demonstrate that immunization with two of the domains can provide protection against invasive amebiasis, that vaccination with the third domain is completely ineffective, and that vaccination with the fourth domain actually exacerbates amebic liver abscess formation. Strikingly, these results can be shown to be dependent on the antibody response, since passive immunization of SCID mice with serum derived from animals vaccinated with the individual domains reproduces the results seen with active immunization. Using synthetic peptides we have also been able to demonstrate that a protective immune response after vaccination with one of the recombinant lectin domains is most likely based on the development of an antibody response to an epitope(s) contained within a stretch of 25 amino acid (aa)1 residues. The clinical relevance of these data has been indicated by our findings that serum samples from asymptomatic individuals colonized with E. histolytica who appear to be resistant to invasive amebiasis show a high level of reactivity with one of the protective domains, while only a few individuals with a history of invasive amebiasis show antibodies to this domain. Finally, we have found that one of the protective domains of the molecule is also a potent T cell mitogen, suggesting that it contains the carbohydrate binding site of the ameba lectin.
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