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-?, 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.
There is currently no vaccine and only a single drug class to treat intestinal amebiasis, one of the leading causes of severe diarrhea in the developing world. An understanding of the human inflammatory response toward Entamoeba histolytica would greatly enhance our ability to develop effective immunotherapies. The studies proposed here will expand the current knowledge of E. histolytica-host interactions, allowing for immune modulating therapies or novel vaccination strategies.
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