Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C. elegans

Distinguishing infectious pathogens from harmless microorganisms is essential for animal health. The mechanisms used to identify infectious microbes are not fully understood, particularly in metazoan hosts that eat bacteria as their food source. Here, we characterized a non-canonical pattern-recognition system in Caenorhabditis elegans (C. elegans) that assesses the relative threat of virulent Pseudomonas aeruginosa (P. aeruginosa) to activate innate immunity. We discovered that the innate immune response in C. elegans was triggered by phenazine-1-carboxamide (PCN), a toxic metabolite produced by pathogenic strains of P. aeruginosa. We identified the nuclear hormone receptor NHR-86/HNF4 as the PCN sensor in C. elegans and validated that PCN bound to the ligand-binding domain of NHR-86/HNF4. Activation of NHR-86/HNF4 by PCN directly engaged a transcriptional program in intestinal epithelial cells that protected against P. aeruginosa. Thus, a bacterial metabolite is a pattern of pathogenesis surveilled by nematodes to identify a pathogen in its bacterial diet. [Display omitted] •PCN, a metabolite secreted by P. aeruginosa, activates innate immunity in C. elegans•The C. elegans nuclear hormone receptor NHR-86 is the sensor for PCN•PCN binds to NHR-86 and activates its anti-pathogen transcriptional program•PCN is surveilled by C. elegans to assess the relative threat of virulent P. aeruginosa Immune sensing of infectious microorganisms is essential for animal health. Peterson and Tse et al. characterize a non-canonical pattern recognition system that intercepts pathogen-derived signals of growth and virulence to assess the relative threat of virulent bacteria. A C. elegans nuclear hormone receptor senses phenazine-1-carboxamide (PCN), a toxic metabolite produced by pathogenic strains of Pseudomonas aeruginosa, to activate innate immunity.