Grant: Operating Grant - Priority Announcement: Infection and Immunity (Bridge Funding)

The ability to efficiently sequence animal genomes has revolutionized the use of simple invertebrate models for studying problems of human immunity. The sea urchin shares many genes with humans that are absent in more distant invertebrate models. The structural simplicity of its feeding larval stage provides an outstanding and unique model for understanding the regulation of gene expression in the context of gut-associated immunity. The sea urchin larva contain many orders of magnitude fewer cells than any vertebrate model yet uses many of the same genes to regulate immunity. We have identified a core set of regulatory factors that are shared between the sea urchin larval immune system and the gut associated immune system of humans. These genes include developmental gene regulatory factors that are associated with normal blood cell production and leukemia, recognition proteins that are associated with inflammatory disease and cell signaling molecules which are associated with autoimmunity. Here we propose to use the expression of a central immune signaling factor (IL17) as an anchor point for understanding the coordination of immune response across the gut epithelium. We will approach this problem with three strategies: (1) we will perturb microbial recognition factors to understand their role in initiating a gut immune response, (2) we will modulate the expression of IL17 to investigate its role in the recruitment and activation of immune cells and (3) we will exploit the simplicity of the larval system to identify new genes that correlate with the expression of the core factors in our gut infection model and function within the same system. Analysis of the sea urchin genome sequence has shown that immunity in this model system is rooted in an ancient control system that is shared with humans. Characterizing this system will lend fresh insight into this fundamental immune function and provide a basis for developing new approaches to controlling disease.