Pathogenesis of Giardia infections: A model to study host-microbial interactions in the gut

点击翻译按钮获取中文摘要

Intestinal disorders and diarrhea are the most common causes of death in many animal species, including humans. Fundamental principles of intestinal function and dysfunction must be further explored. Giardia sp., the most common waterborne parasite in North America, is a significant cause of diarrhea, but the biology of this parasite is incompletely understood. Giardia causes diarrhea in a broad range of hosts, including domestic animals, wildlife, and humans, and there are growing concerns about the zoonotic transmission of this parasite, which was recently included in the WHO "neglected disease initiative". Key mechanisms seen in giardiasis are shared with food allergy, bacterial enteritis, inflammatory bowel diseases, and irritable bowel syndrome, making the study of this parasite an ideal model system for research into fundamental gut pathophysiology. To date, G. duodenalis has been reported to exist in 7 distinct genetic "Assemblages". Reports from around the World have attempted, unsuccessfully, to correlate parasite Assemblage with pathogenesis, and the role of Assemblage -specific effects on acute and post-infectious intestinal dysfunction has yet to be defined. Importantly, Giardia infection does not trigger any overt inflammatory cell infiltration for obscure reasons, which may reflect unrecognized fundamental processes through which inflammation may be subdued in the gut. The objective of the present grant is to identify new mechanisms of gut dysfunction by investigating the pathogenesis of giardiasis. The project will use an established international collaborative network to access state-of-the art methodology, in an attempt to develop synergy and maximize innovation. Over the next 5 years, this project has 4 short term objectives: 1) To identify new Assemblage -specific pathogenic mechanisms, 2) To characterize pathophysiological processes causing post-infectious intestinal dysfunction, 3) To uncover mechanisms of parasite-induced anti-inflammatory signaling in the gut, and 4) To assess the anti-infective effects and mode of action of a novel EGF-enriched whey extract in calves. The findings will shed new light on fundamental biological pathways maintaining gut homeostasis, in domestic animals and humans.