Type 1 interferon-dependent repression of NLRC4 and iPLA2 licenses down-regulation of Salmonella flagellin inside macrophages

Significance 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.