The inverse correlation between exposure to helminths and the incidence of certain immune-mediated diseases, including inflammatory bowel diseases (IBD), evidenced from epidemiological studies (i.e. the hygiene hypothesis), has provided the framework for the pioneering studies of Weinstock et al. and shows promise of using helminths to treat Crohn's disease patients. It has become clear that the chronic inflammation observed in the intestines of IBD patients is due to an aberrant immune response to enteric bacteria. Our understanding of the exact mechanism by which helminths modulate the mucosal response to enteric bacteria is incomplete. Further, the distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, such as HIV, malaria, tuberculosis and infantile diarrhea (caused by enteropathogenic Escherichia coll, EPEC). In many parts of the world, coinfections are also very common. In order to dissect the mechanisms by which helminths modulate the host's response to concurrent pathogens and enteric bacteria, we have established a co-infection model, which involves two murine enteric infectious agents that induce distinct Th responses. We have found that co-infection of mice with the helminth (Heligmosomoides polygyrus) and the enteric bacteria (Citrobacter rodentium) promotes bacterial infection and enhances bacteria-induced colitis. We also observed that dendritic cells (DCs, the most potent antigen-presenting cells), which are primed by the helminth are capable of altering the host's response to the bacteria. Moreover, our preliminary results suggest a role for Th2 cytokine-stimulated macrophages in impairing host defense and promoting TNF-a production, Our overall hypothesis is that intestinal helminth infection can act as a risk factor for enteric bacterial infection and bacteria-associated intestinal inflammation by affecting innate immune cells, resulting in impaired protective immunity and increased tissue injury. Therefore, the objective of this proposal is to explore the mechanisms by which intestinal helminths modulate bacteria-associated intestinal inflammation.
Specific Aim 1 is designed to characterize the helminth-induced alterations in DC phenotype and function that are responsible for impairing the host defense and modulating the pathogenesisi of bacteria-mediated intestinal injury.
Specific Aim 2 is designed to determine the role of helminth-primed DCs in the modulation of mucosal T responses to C. rodentium and the contribution of Th2 cytokine-stimulated macrophages to the alterations in host response to concurrently exposed bacterial pathogens. A better understanding of immunomodulatory effects of helminth will provide information for establishing novel and more effective treatments for immune- mediated diseases, such as IBD, and for the design of effective intestinal vaccines for the prevention and treatment of microbial diseases in the areas where multiple infections exist. ? ? ?
| Su, Chien-wen; Cao, Yue; Zhang, Mei et al. (2012) Helminth infection impairs autophagy-mediated killing of bacterial enteropathogens by macrophages. J Immunol 189:1459-66 |
| Foye, Ondulla T; Huang, I-Fei; Chiou, Christine C et al. (2012) Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling. FEMS Immunol Med Microbiol 65:467-80 |
| Su, Chien-wen; Cao, Yue; Kaplan, Jess et al. (2011) Duodenal helminth infection alters barrier function of the colonic epithelium via adaptive immune activation. Infect Immun 79:2285-94 |
| Wang, Li Jian; Cao, Yue; Shi, Hai Ning (2008) Helminth infections and intestinal inflammation. World J Gastroenterol 14:5125-32 |
