IMMUNITY TO PARASITIC INFECTION

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This proposal would carry forward studies of acquired intestinal immunity to Trichinella spiralis in a model system using rats. The focus of the inquiry has concerned the antibody dependent resistance to T. spiralis that is transferred passively from a specifically immunized mother to her young. This model is novel in that protective intestinal immunity is induced by parenteral immunization. Furthermore, a dramatic and immediate expulsion ("rapid expulsion") of parasites is expressed in the intestines of pups passively immunized with monoclonal IgG antibodies. These antibodies bind glycans presented on the surfaces of larvae and also on glycoproteins found in their secretions. Protective antibodies do not prevent the parasite from entering its intestinal niche, but rather dislodge it from that site, in order to effect expulsion. In certain instances, antibodies affect the ability of larvae to move freely in the epithelium, but do not expel them. Our objectives are to elucidate the mechanisms by which antibodies immobilize and/or dislodge larvae from their epithelial niche and to identify and functionally characterize the molecular target(s) of these antibodies. Monoclonal antibodies which immobilize and dislodge T. spiralis larvae from intestinal epithelia would be used in vivo and in vitro in order to study the mechanism by which antibodies perturb the balance maintained by parasite and host in the epithelium. Experiments are proposed to test a series of hypotheses which concern the behavior of T. spiralis in the epithelium as well as the essential interactions between parasite and host. These hypotheses state that protective antibodies: 1) effect immunity by binding to secreted and not surface antigens; 2) interfere with the migration of larvae through the epithelium; 3) divert larvae from their niche; 4) block interaction of parasite antigens with host cell components; 5) depend upon Fc receptors expressed on intestinal epithelia in neonatal and adult rats and mice. We would apply our findings to studies of protective immunity against another nematode, Trichuris muris. The composition of the target antigen(s) would be revealed in biochemical and genetic investigations. The structures of the glycans bound by protective antibodies would be determined and fragments of the glycans synthesized in order to dissect their role in parasite establishment. We would continue to clone and express the genes which encode peptide portions of antigenic glycoproteins, testing recombinant antigens for immunogenicity. These investigations are designed to identify and characterize the molecules produced by the parasite and the host that are required for successful parasitism by an intestinal nematode.