Monounsaturated fatty acid depletion is a metabolic pattern of pathogenesis surveilled to activate p38 MAPK innate immunity

Pathogen infection profoundly remodels host metabolism. Whether hosts sense specific pathogen-induced metabolic changes to identify microbial infection is not known. Here, we find that depletion the monounsaturated fatty acid oleate is a metabolic pattern of pathogenesis, specifically surveilled by the nematode C. elegans to identify active infection with a bacterial pathogen. We previously demonstrated that the enzymatic TIR (Toll/interleukin-1 receptor/resistance)-domain containing protein, TIR-1/SARM1, the key upstream activator of p38 MAPK PMK-1 immunity, is a guard protein in an effector-triggered immune response, positioned specifically on the surface of lysosome-related organelles to sense the toxic effects of bacterial infection. Here, we show that acute loss of oleate in intestinal cells during bacterial infection causes lysosome-related organelles to collapse, which induces the aggregation and activation of TIR-1/SARM1. Further, we find that oleate deficiency is a host vulnerability that concomitantly activates the c-Jun N-terminal kinase (JNK) KGB-1 nutrient sensing pathway, an adaptive response that promotes expression of TIR-1/SARM1 on lysosome-related organelles and is required for survival during infection. These data establish a mechanistic connection between fatty acid nutrition and innate immune regulation, and reveal that specific changes in host metabolism are surveilled to identify pathogen attack.