Activation of intestinal immunity by pathogen effector-triggered aggregation of lysosomal TIR-1/SARM1

Abstract

SUMMARYMechanisms of pathogen recognition in barrier tissues, which interface with both commensal and virulent bacteria, are critical for health and not fully understood. Here, we discovered a central role for lysosome-related organelles in innate immune sensing and p38 innate immune activation in intestinal epithelial cells, which enables the nematodeC. elegansto survey for the effects of a bacterial pathogen on the host to activate protective anti-pathogen defenses. We showed that the conserved immune signaling regulator TIR-1/SARM1 is expressed on the membranes of lysosome-related organelles. Pyocyanin, a virulence effector secreted byPseudomonas aeruginosa,alkalinized and collapsed lysosome-related organelles, triggering TIR-1/SARM1 multimerization to activate the p38 innate immune pathway. Thus, pathogen effector-mediated collapse of lysosome-related organelles is an initiating event of innate immune sensing and p38 activation, which allowsC. elegansto identify a pathogen through its effects on host physiology.