Investigating cross-regulation of the microbiome and mucosal immune system using humanized mice

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 DESCRIPTION (provided by applicant): In the intestine, exposure to commensal microbes early in life is a key determinant in the development of mucosal immune tolerance and homeostasis. Dysfunction of tolerogenic and homeostatic immune pathways underlies a broad variety of chronic inflammatory disorders, including not just Crohn's disease and ulcerative colitis, but also allergy, and even colorectal cancer. The immune dysfunction associated with such disorders is complex and still incompletely understood, and further defining these mechanisms is of significant clinical relevance. In recent years the role of the microbiome in human health and disease has become an area of intense focus. Although sequence profiling of the human microbiome has characterized the microbial communities present at mucosal interfaces in health and disease, our understanding of the relationship between the human intestinal microbiome and human mucosal immune system remains incomplete. Genome-wide association studies have identified numerous polymorphisms that are associated with altered risk for inflammatory bowel disease (IBD), many of which are involved in host defense and may contribute to dysbiosis, a well-established hallmark of IBD. It is not known if dysbiosis is caused by these variants or is a result from underlying inflammation. Similarly, it is unknown whether alterations in the microbiome of IBD patients are sufficient to promote immune dysregulation. Experimental murine models have given some insight but disease signatures in murine models of inflammation often poorly correlate with human disease. Furthermore, it has been shown that development and maturation of the murine mucosal immune system requires host-specific gut microbiome necessitating novel experimental systems to investigate human immunobiology. My goal is to understand the cross-regulation between the human mucosal immune system and human microbiome. I have developed a novel humanized mouse strain that displays adaptive immune responses and can recapitulates a human immune disease when using HSCs with mutated FOXP3. I have re-derived this strain into germ-free conditions to permit defined colonization strategies to investigate human mucosal immune development/function and the dynamics of the human intestinal microbiome providing an opportunity to characterize the developing human mucosal immune system not previously achieved in experimental models. My hypothesis is that both genetic susceptibility and dysbiosis alter mucosal immune development and contributes to aberrant immune responses in the intestine and I will address this in three aims: 1) whether dysbiosis impacts human mucosal immune system 2) whether genetic susceptibility perturbs microbiome stability; 3) whether exogenous administration of microbial byproducts or metabolites potentiates human Treg development.