The NLRC4 inflammasome regulates extra- and intra-macrophage expression of its own pathogen-derived ligand flagellin to impact Salmonella survival.

Abstract

Abstract Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but whether the process of inflammasome activation per se regulates expression of microbial effectors is unknown. Here we show that inflammasome activation regulates expression of the NLRC4 ligand, flagellin, on Salmonella. Lysophospholipids released upon macrophage pyroptosis increase expression of flagellin on Salmonella and its ability to induce further NLRC4 inflammasome-dependent pyroptosis, establishing a positive feedback loop that potentiates Salmonella detection and clearance. As infection progresses, this positive feedback is checked by inhibition of NLRC4 expression and lysophospholipid biosynthesis, thus switching Salmonella to a flagellin-negative phenotype inside macrophages. While inhibition of inflammasome activation could be a host strategy aimed at preventing overt cell death and enabling generation of a productive adaptive immune response post infection, our study demonstrates that Salmonella hijacks this host response to facilitate its intracellular survival. Our data reveal a host-dependent mechanism by which Salmonella downregulates flagellin within macrophages and identify the modulation of expression of a pathogen-derived inflammasome ligand by the very process of inflammasome activation as a novel mode of host-pathogen cross talk during infection with a bacterial pathogen.