A host cell-intrinsic innate regulatory circuit limits inflammasome activity and promotes immune escape of Salmonella inside macrophages

Abstract

Abstract Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether there is active cross-talk between the host sensing mechanism and the expression of stimulatory ligands by the pathogen. Here we show that inflammasome activation regulates expression of the NLRC4 and TLR5 ligand, flagellin, by Salmonella. Host lysophospholipids released upon NLRC4-mediated pyroptosis increase flagellin expression by extracellular bacteria that enhances pyroptosis upon internalization, establishing a positive feedback loop that potentiates Salmonella detection and clearance. A TLR-dependent host negative feedback response later inhibits inflammasome activation and lysophospholipid biosynthesis within cells, prompting the pathogen to switch to a flagellin-low phenotype and establish an intracellular survival niche inside macrophages. Ablation of this host regulatory circuit prevents downregulation of flagellin by intracellular Salmonella and promotes bacterial clearance in vivo. Our data identify modulation of expression of a bacterium-derived inflammasome ligand by the very process of inflammasome activation as a novel mode of host-pathogen cross-talk and reveal a host mechanism that is adapted by Salmonella for flagellin downregulation and immune escape within macrophages.