Role of the Pro-inflammatory MIF Homolog of Entamoeba histolytica in Colitis

项目摘要 方法：我们建议检验这一假设，即溶组织内阿米巴上游的同源物 促炎症细胞因子巨噬细胞移动抑制因子(EhMIF)介导的破坏性炎症 阿米巴结肠炎的反应。我们进一步假设EhMIF诱导肠道产生IL-8 上皮细胞导致炎性细胞向肠粘膜募集。此外，我们预测 EhMIF刺激肠粘膜炎症细胞产生过量的肿瘤坏死因子-α、IL-6和IL-23 这会破坏粘膜屏障。 该提案的创新方面包括，它探索了一种潜在的新的寄生虫诱导的介体 未被充分研究的组织部位的损伤：寄生虫MIF同源物对肠黏膜炎症的影响 而感染过程中的损伤是未知的，并挑战了肠粘膜损伤的主导范式 由溶组织性肠杆菌直接杀死宿主细胞的结果。 这些研究的成功完成将促进我们对寄主-E。溶组织性相互作用 并可能转化为免疫调节疗法和疫苗接种的新方法。 意义：这项工作意义重大，因为腹泻是#年导致死亡的第二大原因。 全球五岁以下儿童，肠道阿米巴病是全球严重腹泻的主要原因之一。 发展中世界。目前没有疫苗，只有一类药物，硝基咪唑，以达到 治疗这种毁灭性的疾病。 这项工作的环境包括加州大学一流的学术传染病项目 弗吉尼亚州，一个在人类、小鼠模型和细胞中积极调查溶组织埃希氏菌的计划 和我的导师(佩里医生)，他和我一样是一名传染病临床医生，他的贡献 阿米巴结肠炎研究超过25年。 K08：我在这份建议书中的职业发展计划将通过 我的内部和外部咨询团队、课程、技术支持的有力指导和支持相结合 以免疫学和宿主-病原体相互作用为重点的培训、研讨会和会议，所有这些都将 帮助我成为一名独立的临床医生兼科学家。

Project Summary Approach: We propose to test the hypothesis that the Entamoeba histolytica homolog of the upstream proinflammatory cytokine macrophage migration inhibitory factor (EhMIF) mediates a destructive inflammatory response in amebic colitis. We further hypothesize that EhMIF induces IL-8 production from intestinal epithelial cells resulting in recruitment of inflammatory cells to the intestinal mucosa. Additionally, we predict that EhMIF stimulates inflammatory cells in the intestinal mucosa resulting in excess TNF-α, IL-6 and IL-23 that disrupt the mucosal barrier. Innovative aspects of the proposal include that it explores a potentially novel mediator of parasite-induced injury at an understudied tissue site: the effect of parasite MIF homologs on intestinal mucosal inflammation and injury during infection is not known, and challenges the dominant paradigm that intestinal mucosal injury is a result of direct killing of host cells by E. histolytica. Successful completion of these studies will advance our understanding of the host-E. histolytica interactions and may translate into new approaches to immune-modulating therapies and vaccination. Significance: The work is significant because diarrheal disease is the second leading cause of death in children under five globally, and intestinal amebiasis is one of the main causes of severe diarrhea in the developing world. There currently exists no vaccine and only a single class of drugs, the nitroimidazoles, to treat this devastating disease. The environment for the work includes the superb academic infectious diseases program of the University of Virginia, a program of active investigation of E. histolytica in humans, murine models, and at the cellular level, and my mentor (Dr. Petri) who like myself is an infectious diseases clinician, and who has contributed to amebic colitis research for over 25 years. K08: My career development plan in this proposal will augment the success of this project through the combination of strong guidance and support from my internal and external advisory teams, courses, technical training, seminars and conferences focusing on immunology and host-pathogen interactions, all of which will help establish me as an independent clinician-scientist.