We hypothesize that intestinal colonization with the human commensal Clostridium scindens epigenetically alters the bone marrow to increase granulocyte precursors that protect the gut from parasite infection. We will test our hypothesis via two complementary aims.
In Aim 1 Test if C. scindens-mediated protection is dependent on bone marrow derived cells.
In Aim 2 Determine if C. scindens epigenetically alters genes important in generation or recruitment of gut myeloid cells via JMJD3. Successful completion of these studies: will identify how intestinal Clostridia induce epigenetic changes in the bone marrow that in turn induce gut antigen-nonspecific ?trained innate immunity?. Significance: There is an urgent need for novel approaches to treat or prevent Entamoeba histolytica as it is an important cause of diarrhea in infants in low income countries. There is no vaccine and only a single class of antiparasitics effective for invasive amebiasis. Innovation: This work will provide a robust understanding of Clostridium scindens-mediated protection from amebiasis and provide understanding of fundamental processes underlying innate trained immunity induced by the host microbiota. Novel theoretical concepts derived from this work will identify pathways important in microbiota-mediated protection from parasite infection that can be targeted by translational medicine. The environment for this work is a research group dedicated to the study of the pathogenesis of amebic colitis for the last 25 years. Our work has described the natural history of amebiasis in children and adults, developed the amebiasis mouse model, and led to understanding of innate and acquired immunity to E. histolytica.
This project investigates how the gut microbiota trains the innate immune system to protect from amebic colitis. We have discovered that commensal Clostridia bacteria in the gut microbiome protect from E. histolytica colitis. We hypothesize that protection is due to the gut responding to the presence of Clostridia by epigenetically altering the bone marrow to increase granulocyte-monocyte progenitors. This results in increased neutrophils trafficking back to the gut to protect from E. histolytica. Successful completion of our proposal will offer the potential to prevent amebiasis by the use of commensal Clostridia as probiotics, as well as be of general importance for the understanding of regulation of inflammation in the intestine.
