PmiR senses 2-methylisocitrate levels to regulate bacterial virulence in Pseudomonas aeruginosa
Guoyan Cui1, Yixi Zhang2, Xuejie Xu1
1Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, ShaanXi, China.
Abstract:
To adapt to changes in environmental cues, Pseudomonas aeruginosa 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 P. aeruginosa 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 pqs quorum-sensing system and subsequently inhibited pyocyanin production. Moreover, mutation of pmiR reduces bacterial survival in a mouse model of acute pneumonia infection. Collectively, this study identified P. aeruginosa PmiR as an important metabolic sensor for regulating expression of bacterial virulence genes to adapt to the harsh environments.
Insights
Pseudomonas aeruginosa uses PmiR as a sensor for 2-methylisocitrate (MIC) to control virulence. This discovery reveals how the bacterium adapts to host environments by regulating virulence factors.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Pseudomonas aeruginosa employs diverse virulence factors to combat host defenses.
- Metabolic products significantly influence bacterial virulence, yet their signaling receptors are not fully understood.
- Understanding metabolic regulation of virulence is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of the 2-methylcitrate cycle in P. aeruginosa virulence.
- To identify and characterize the receptor for 2-methylisocitrate (MIC).
- To elucidate the mechanism by which MIC signaling impacts bacterial virulence gene expression.
Main Methods:
- Characterization of the 2-methylcitrate metabolic pathway in P. aeruginosa.
- Crystallographic studies and site-directed mutagenesis to analyze PmiR-MIC interactions.
- Assessment of PmiR's effect on the pqs quorum-sensing system and pyocyanin production.
- Evaluation of P. aeruginosa virulence in a mouse model of pneumonia.
Main Results:
- PmiR was identified as the receptor for 2-methylisocitrate (MIC).
- Structural analysis revealed key residues mediating PmiR's allosteric activation by MIC.
- PmiR was shown to directly repress the pqs quorum-sensing system, inhibiting pyocyanin production.
- Mutations in pmiR impaired bacterial survival in a mouse pneumonia model.
Conclusions:
- P. aeruginosa PmiR acts as a critical metabolic sensor for 2-methylisocitrate.
- PmiR regulates bacterial virulence by repressing the pqs quorum-sensing system.
- This metabolic sensing pathway is essential for P. aeruginosa adaptation and survival during infection.
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