While the effect of bacterial molecules on the host immune system is well studied, how host factors affect the expression of bacterial molecules is less appreciated. Here we uncover the impact of inflammasome activation and type 1 interferon on the expression of bacterial flagellin. Flagellin induces NLRC4 inflammasome-mediated pyroptosis causing clearance of Salmonella. We show that inflammasome activation also produces lysophospholipids which increase flagellin expression by Salmonella early in infection. We further demonstrate that as infection progresses, type 1 IFN inhibits NLRC4 and lysophospholipid synthesis, resulting in down-regulation of flagellin expression, a phenotype that the pathogen switches to during establishment of in vivo infection. These findings unravel pathways for biphasic regulation of expression of flagellin, a key Salmonella effector.
Abstract
Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection with Salmonella and many other pathogens, flagellin is a major activator of NLRC4 inflammasome-mediated macrophage pyroptosis and pathogen eradication. Salmonella switches to a flagellin-low phenotype as infection progresses to avoid this mechanism of clearance by the host. However, the host cues that Salmonella perceives to undergo this switch remain unclear. Here, we report an unexpected role of the NLRC4 inflammasome in promoting expression of its microbial ligand, flagellin, and identify a role for type 1 IFN signaling in switching of Salmonella to a flagellin-low phenotype. Early in infection, activation of NLRC4 by flagellin initiates pyroptosis and concomitant release of lysophospholipids which in turn enhance expression of flagellin by Salmonella thereby amplifying its ability to elicit cell death. TRIF-dependent production of type 1 IFN, however, later represses NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2, causing a decline in intracellular lysophospholipids that results in down-regulation of flagellin expression by Salmonella. These findings reveal a previously unrecognized immune-modulating regulatory cross-talk between endosomal TLR signaling and cytosolic NLR activation with significant implications for the establishment of infection with Salmonella.
