Metabolic Regulation of Immunity in C. elegans

Dysregulation of fundamental signaling pathways due to perturbations of cellular metabolites can have devastating consequences for human health. For example, inborn errors of purine metabolism cause alterations in levels of purine nucleotides and their metabolites, resulting in a variety of disorders ranging from seizures to immunodeficiency and, in severe cases, premature death. The genetic and biochemical experiments described in this proposal will elucidate how purine nucleotide metabolism regulates intestinal epithelial defense pathways in the model organism C. elegans. The epithelium is the first line of defense against pathogen attack, and it is vital that we fully understand the mechanisms by which it actively targets pathogens, especially intracellular pathogens like viruses. Due to the lack of professional immune cells, C. elegans is an ideal system for studying epithelial defense pathways. First, we focus on understanding how purine metabolites regulate the transcription of genes that compose the Intracellular Pathogen Response, a type I interferon-like defense program, in the C. elegans intestine. To further understand purine metabolism, we will develop tools to visualize purine nucleotide metabolic flux in the intestine to determine how it is regulated and how it regulates other pathways. Finally, we will widen our metabolic scope by investigating the impact of modifying defense proteins with the metabolite uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the final metabolite of the hexosamine biosynthetic pathway. UDP-GlcNAc is the sole source used to generate the post-translational modification O-linked GlcNAc (O-GlcNAc). Dysregulation of O-GlcNAc has been implicated in many disorders, such as cancer, diabetes, autoimmunity, and Alzheimer's. In the C. elegans intestine, we will determine how O-GlcNAc regulates the function of highly conserved RNA interference proteins using genetic and biochemical techniques. Our studies elucidating the mechanisms by which conserved metabolites regulate fundamental epithelial defense functions in the genetically tractable C. elegans model will provide insights into conserved processes in vertebrates and identify metabolites that could serve as targets for interventions to treat human diseases. Project Number: 1R35GM161455-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Eillen Tecle | Institution: MEDICAL COLLEGE OF WISCONSIN, MILWAUKEE, WI | Award Amount: $390,000 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11259771