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 belongs to the sister-group of the animal phylum that includes ourselves and as such it shares many gene counterparts with humans that are absent in commonly used divergent invertebrate models. The structural simplicity of its feeding larval stage provides an outstanding model for understanding regulation of gene expression in the context of immunity. A remarkable outcome of our analysis of the sea urchin genome sequence is the finding of a 20-fold expansion in the number of genes encoding important immune receptors known as Toll-like receptors (TLRs) than is found in vertebrates. This gene family offers experimental opportunities to understand function of this important group of immune recognition factors. Here we propose to investigate the function of this novel gene family in detail by (1) further resolving the genomic sequence for key TLR families, (2) characterizing expression of TLR subtypes to understand how this genetic diversity is distributed among immune cells, (3) carrying out functional assays to understand how the TLRs interact with each other and with immune signaling proteins and (4) investigating these receptors in the context gene expression control programs in the larval model system. The genome sequence indicates that sea urchins have devised a novel approach to immunity that is nonetheless rooted in an ancient control system that they share with humans. Characterizing this system will lend fresh insight into the function of these very important TLR receptors and provide a basis for developing new approaches to controlling infection and autoimmunity.