PmiR senses 2-methylisocitrate levels to regulate bacterial virulence in <i>Pseudomonas aeruginosa</i>.

Abstract

To adapt to changes in environmental cues, <i>Pseudomonas aeruginosa</i> produces an array of virulence factors to survive the host immune responses during infection. Metabolic products contribute to bacterial virulence; however, only a limited number of these signaling receptors have been explored in detail for their ability to modulate virulence in bacteria. Here, we characterize the metabolic pathway of 2-methylcitrate cycle in <i>P. aeruginosa</i> and unveil that PmiR served as a receptor of 2-methylisocitrate (MIC) to govern bacterial virulence. Crystallographic studies and structural-guided mutagenesis uncovered several residues crucial for PmiR's allosteric activation by MIC. We also demonstrated that PmiR directly repressed the <i>pqs</i> quorum-sensing system and subsequently inhibited pyocyanin production. Moreover, mutation of <i>pmiR</i> reduces bacterial survival in a mouse model of acute pneumonia infection. Collectively, this study identified <i>P. aeruginosa</i> PmiR as an important metabolic sensor for regulating expression of bacterial virulence genes to adapt to the harsh environments.