Immunity to Parasitic Infection

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DESCRIPTION (provided by the applicant): The epithelial barrier in the intestine is crucial to survival. Intestinal nematodes deploy novel tools to live in this site. In turn, immunity to parasitic nematodes has a set of novel parameters. Our objective is to elucidate mechanisms of protective, intestinal immunity against parasitic nematodes. Rapid expulsion is a potent immune phenomenon that protects rats against secondary infection by Trichinella spiralis. We have shown that IgG antibodies, specific for tyvelose-capped glycans on larval excretory-secretory products, expel larvae from suckling rats. Expulsion by adult rats is also dependent upon anti-tyvelose IgG but requires cooperation with an unidentified innate component. Evidence suggests that the essential innate constituent is the mucosal mast cell. The mechanism of immunity is unknown. Our ability to reproduce the epithelial habitat of T. spiralis in vitro affords us a unique opportunity to investigate the cooperative, protective activities of cells and antibodies. Our specific aims will test the following hypotheses: 1. Activation of mucosal mast cells by immune complexes is isotype dependent. Immune complexes formed with monoclonal anti-tyvelose IgGs will be tested for receptor binding, degranulation and cytokine induction with rat mucosal mast cells. Mast cells will be treated with cytokines that are produced locally during infection in order to induce cellular properties that may contribute to intestinal immunity. 2. Activation of mucosal mast cells disrupts the epithelial habitat of T. spiralis. The intestinal habitat of T. spiralis will be modeled in vitro in order to dissect mast cell activities that promote parasite expulsion. The workings of specific and non-specific mediators that compromise the epithelial habitat of T. spiralis will be defined. 3. Mast cells and anti-tyvelose IgG mediate rapid expulsion in vivo. Mast cell deficient rats will be infected to test the contribution of mast cells to rapid expulsion in vivo. We will recreate the immune intestine by eliciting mastocytosis in rats independently of intestinal T. spiralis, and then passively immunizing rats with tyvelose specific antibodies. The work we propose will elucidate a potent mechanism of intestinal immunity and will improve our ability to develop novel vaccines for intestinal pathogens.