Role of CREM in Amebic Colitis and Inflammatory Bowel Disease

Approach: We propose to continue our study of how the human transcription factor CR E M (cAMP responsive element modulator) contributes to the innate immune response to protect from colitis due to E ntamoeba histolytica and further explore its role in inflammatory bowel disease. Successful completion of these studies will identify how and where CR E M acts to guard against bowel injury from amebiasis, and link the findings to inflammatory bowel disease. Significance: The importance of this project derives from the contribution of amebiasis to diarrhea in children in the developing world and to the estimated one million Americans who suffer from IBD. Understanding how CR E M protects may provide new approaches to the currently imperfect treatments of amebic colitis and IBD. Progress: The past 3.5 years of R37 support advanced the unde rstanding of amebic colitis and resulted in 8 publications, including the identification of CR E M as a susceptibility locus for amebiasis, demonstration of microbiome to bone marrow communication via the secondary bile acid deoxycholate in resistance to amebiasis, and the role of innate lymphoid cell type 2 in directing a protective type 2 innate response to the parasite. Additional discoveries include human genes influencing susceptibility to cryptosporidiosis and shigellosis. Innovative aspects of the proposal include that cAMP-regulated gene expression has not previously been considered to contribute to defense of the intestine. The environment for the work is Dr. Petri's parasitology lab (UVA) with ongoing investigation of amebiasis in humans, murine models and at the cellular level, and the human genetic epidemiology program of Dr. Duggal (Hopkins) and the now twenty year collaboration between Drs. Duggal and Petri that has resulted in 21 publications. I I RELEVANCE (See instructions): This project investigates how a human transcription factor named CR E M protects from amebic colitis. We have discovered a genetic mutation in CR E M that is associated with susceptibility to E ntamoeba histolytica colitis and inflammatory bowel disease (IBD). Understanding how CR E M protects will provide new advances in the treatment of amebic colitis and IBD.