Evidence from epidemiological studies indicates an inverse correlation between the incidence of certain immune-mediated diseases, including inflammatory bowel diseases (IBD), and exposure to parasitic helminths. Helminth infections are known to dampen Th1 reactions, a characteristic that has potential use in the treatment of Th1-mediated autoimmune and inflammatory conditions. However, our understanding of the exact mechanism by which helminths modulate mucosal responses is incomplete. Using our recently established co- infection model, we found that intestinal helminth infection exacerbates colitis induced by concurrent infection with the bacterial enteric pathogen Citrobacter rodentium. Additional preliminary results from studies using a T cell-mediated colitis model provide evidence to indicate that a simultaneous helminth infection also enhances intestinal inflammation in SCID mice that are adoptively transferred with ovalbumin (OVA) specific T cells and infected orally with OVA expressing E. coli. Helminth-induced exacerbation of intestinal inflammation has also been reported in an inducible colitis model. The differences in the effects of helminths in various models of intestinal inflammation emphasize the need for a better understanding of the mechanisms by which helminths modulate host mucosal immunity. Our observations of deleterious consequences of helminth parasites in both bacterial and T cell mediated intestinal inflammation support our overall hypothesis that helminth infection may be a potential risk factor for the development and progression of such diseases. Experiments proposed in this application address the idea that the exacerbating effect on intestinal inflammation is the consequence of helminth induced (1) modulation of T cell function to a phenotype that promotes pro-inflammatory responses, in part by impairing intestinal epithelial barrier function and allowing increased translocation of luminal contents, and (2) alterations in macrophage phenotype and function that compromise the ability to eliminate translocated bacteria. We will carry out experiments to explore the mechanism(s) by which enteric helminths modulate intestinal inflammatory responses. We will determine (1) how helminth infection alters the T cell response to a surrogate commensal bacterium (E. coli-OVA) and how helminth-induced dysregulation of T cell response impairs epithelial barrier function;and (2) the effect of helminths on macrophage microbicidal and inflammatory functions. The experiments proposed will provide new insight into the mechanism by which helminths modulate intestinal responses to luminal bacterial antigens, and facilitate the development of novel, safer and more effective treatments for immune-mediated diseases.
The studies outlined in this proposal will determine the immuomodulatory role of intestinal helminth parasites in bacteria-associated and T cell-mediated intestinal inflammation. We will carry out experiments to (1) explore the mechanism(s) by which enteric helminth alters the T cell response to the surrogate commensal bacterium (E. coli-OVA);and (2) determine how the helminth-induced Th2 response, in turn, impairs intestinal epithelial barrier function and alters macrophage phenotype and function that compromise the ability to eliminate translocated bacteria, contributing to impaired host defense and increased tissue injury.
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