Comparative functional genomics of innate immunity in deuterostomes

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Animals use an innate immune system to protect themselves from pathogens, such as viruses and bacteria. Receptors of the innate immune system that recognize such pathogens are important for starting the process of pathogen clearance, and are unchanged over an individual's lifetime. Moreover, several genes involved in innate immunity appear to be evolutionarily conserved across major animal groups. Researchers have little understanding of how innate mechanisms of immunity recognize and defend against the wide diversity of microbes and viruses encountered by different animals in different environments. To explore this question, as well as to more fully understand the genetic setting that led to the evolution of the adaptive immune system in vertebrates, researchers will explore the diversity and conservation of innate immune mechanisms across deuterostome animals (a group that includes acorn worms, sea stars, sea cucumbers, sea squirts, and vertebrates). To undertake this work, researchers will employ novel genomic data, develop bioinformatic tools, and use an experimental approach to understand which innate immune genes are activated, or repressed, when various antigens are presented to the study animal. Acorn worms, relatives of chordates for which little is known, will be a main focus of experimental work. Additionally, investigators will train undergraduate and graduate students drawn form diverse backgrounds. Workshops focused on elementary and middle schools students will transfer knowledge and excitement about biodiversity, genomic tools, and immunology.Pattern Recognition Receptor (PRR) pathways are part of an ancient innate immune defense system spanning Metazoa, and are known to react to conserved molecular motifs exhibited by common pathogens (e.g., viruses, bacteria, fungi). Pattern Recognition Receptor-facilitated defenses include pathways initiated by Toll-Like Receptors (TLR), RIG-I like Receptors, and NOD-like receptors. Unfortunately, the evolution of innate immune systems across invertebrates, including the ancestral state for deuterostomes, is unclear. Moreover, the breadth of TLR-facilitated ligand-specificity has been suggested to be fine-tuned to the niche an organism occupies, despite exhibiting evolutionary conservation across lineages and thus, evolutionary time. The functional novelty of Pattern Recognition Receptors, origins or associated pathways, and degree of evolutionary conservation are open questions. This study combines informatics and experimental tools to, 1) gain insight on the ancestral state of innate immunity in hemichordates, ambulacrarians, and ultimately deuterostomes, 2) further understand the setting of organismal pathogen-defense systems preceding the genesis of adaptive immunities, and 3) quantitatively assess variation and divergence of innate immunity elements over evolutionary time. Differential gene expression and in situ hybridization will be used in controlled settings to assess deployment and responsiveness of innate immunity pathways. Functional conservation will be assessed with experimental rescue of human TLR-/- cell lines with the corresponding hemichordate orthologs. The project will promote career development for a Beginning Investigator, graduate students, and undergraduates. A set of outreach workshops (with immunology, genomic and evolution themes) is specifically proposed that will reach K5-8 and their parents. This work seeks to support participation of under-represented groups and summer interns.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.