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

肠道疾病和腹泻是包括人类在内的许多动物物种最常见的死亡原因。肠道功能和功能障碍的基本原理必须进一步探讨。贾第鞭毛虫是北美最常见的水媒寄生虫，是引起腹泻的重要原因，但这种寄生虫的生物学尚不完全清楚。贾第鞭毛虫在包括家畜、野生动物和人类在内的广泛宿主中引起腹泻，人们越来越担心这种寄生虫的人畜传播，这种寄生虫最近被列入世界卫生组织“被忽视的疾病倡议”。贾第鞭毛虫病的关键机制与食物过敏、细菌性肠炎、炎症性肠病和肠易激综合征相同，使对这种寄生虫的研究成为研究基础肠道病理生理学的理想模型系统。到目前为止，十二指肠球虫已被报道存在于7个不同的遗传“组合”中。来自世界各地的报告试图将寄生虫集合与发病机制联系起来，但未获成功，集合特异性效应在急性和感染后肠道功能障碍中的作用尚未确定。重要的是，贾第虫感染不会因为不明原因而引发任何明显的炎症细胞渗透，这可能反映了肠道炎症可能被抑制的未知基本过程。这笔赠款的目的是通过研究贾第鞭毛虫病的发病机制来确定肠道功能障碍的新机制。该项目将利用建立的国际协作网络获取最先进的方法，试图发展协同效应和最大限度地创新。在接下来的5年里，这个项目有4个短期目标：1)识别新的特定集合体的致病机制，2)表征感染后肠道功能障碍的病理生理过程，3)揭示寄生虫诱导肠道炎症信号的机制，4)评估一种新型的富含EGF的乳清提取物在犊牛中的抗感染效果和作用模式。这些发现将为家畜和人类维持肠道内环境稳定的基本生物学途径提供新的线索。

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.