Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity (360G-Wellcome-206245_Z_17_Z)

Intestinal infections affect billions of people worldwide, resulting in nearly 1.4 million deaths each year. The commensal microbiota can prevent pathogenic infection, as demonstrated by increased susceptibility to infection upon antibiotic use; however, the precise mechanisms of microbiota-mediated protection are not well-characterized. I have recently discovered that colonization of mice with commensal Enterococcus faecium leads to improved intestinal barrier function and decreased Salmonella and Clostridium difficile pathogenesis. I went on to uncover a mechanism by which a unique enzyme, SagA, from these bacteria activates intestinal epithelial cells (IECs) to increase anti-microbial peptide (AMP) expression and mucin distribution. These studies revealed several host and microbiota factors involved in pathogen tolerance. My proposed independent research will identify the mechanisms by which commensal bacteria modulate IECs and intestinal immunity. Utilizing advance microscopy, proteomics and sequencing approaches, I will characterize the effects of E. faecium, SagA and other microbiota metabolites on IEC gene expression and function and subsequent pathogen resistance. Using proteomics-based bioorthogonal reporters and intersectional genetics, I will then dissect how microbial modulation of IECs affects the differentiation and function of intraepithelial lymphocytes. Elucidating the IEC programs triggered by commensal bacteria will enable better strategies to prevent and treat intestinal infections.