Bacterial pattern recognition in C. elegans by the nuclear hormone receptor NHR-86/HNF4

Pattern recognition of bacterial products by host receptors is essential for pathogen sensing in many metazoans. Caenorhabditis elegans, however, do not utilize canonical pattern recognition receptors to activate innate immunity toward bacterial pathogens. Whether other mechanisms evolved in nematodes to directly sense pathogens is not known. Here, we characterize the first bacterial pattern recognition receptor and its natural ligand in C. elegans. We show that the C. elegans nuclear hormone receptor NHR-86/HNF4 senses phenazine-1-carboxamide (PCN), a metabolite produced by pathogenic strains of Pseudomonas aeruginosa, to activate protective anti-pathogen defenses in the intestine. PCN binds to the ligand binding domain of NHR-86/HNF4, a ligand-gated transcription factor, which engages a transcriptional program in intestinal epithelial cells that promotes metabolism of toxic phenazines to provide protection against P. aeruginosa. These data de-orphan a nuclear hormone receptor and demonstrate that sensing a metabolite signal of bacterial virulence allows nematodes to detect pathogens in its environment that are poised to cause disease. RNA-seq of C. elegans wild-type (N2) animals exposed to Escherichia coli (OP50), Pseudomonas aeruginosa (PA14)-wt or PA14 Δphz (deletion of both phenazine producing operons) supplemented either with solvent control (DMSO) or PCN (25 μg/mL). RNA-seq of C. elegans wild-type (N2) grown on control RNAi or nhr-86(RNAi) and exposed at L4 stage to Escherichia coli (OP50) supplemented either with solvent control (DMSO) or PCN (25 μg/mL).