The GPCR NMUR-1 mediates neural regulation of energy homeostasis in response to pathogen infection

A key challenge in immunology is understanding how the innate immune system achieves specificity against diverse pathogens. Our previous work in <i>Caenorhabditis elegans</i> identified NMUR-1, a neuronal G protein-coupled receptor homologous to mammalian neuromedin U receptors, as a regulator of pathogen-specific innate immune responses. Here, we used quantitative proteomics and functional analyses to show that NMUR-1 modulates the expression of mitochondrial F₁F_O ATP synthase subunits and regulates ATP levels during infection, linking neuronal signaling to host energy metabolism. Loss of NMUR-1 leads to reduced ATP and reactive oxygen species (ROS) concentrations in infected animals, altering survival outcomes in a pathogen-specific manner. We further demonstrate that ATP availability and its contribution to host defense are neurally controlled by the NMUR-1 ligand CAPA-1 and its source neurons, ASG. These findings uncover a neuroimmune mechanism whereby NMUR-1 regulates energy homeostasis as a determinant of innate immune specificity. Our study also provides mechanistic insights into the emerging roles of conserved NMU signaling in neuroimmune regulation across animal phyla.