Abstract
Pseudomonas aeruginosa defies eradication by antibiotics and is responsible for acute and chronic human infections due to a wide variety of virulence factors. Currently, it is believed that MvfR (PqsR) controls the expression of many of these factors indirectly via the pqs and phnAB operons. Here we provide strong evidence that MvfR may also bind and directly regulate the expression of additional 35 loci across the P. aeruginosa genome, including major regulators and virulence factors, such as the quorum sensing (QS) regulators lasR and rhlR, and genes involved in protein secretion, translation, and response to oxidative stress. We show that these anti-oxidant systems, AhpC-F, AhpB-TrxB2 and Dps, are critical for P. aeruginosa survival to reactive oxygen species and antibiotic tolerance. Considering that MvfR regulated compounds generate reactive oxygen species, this indicates a tightly regulated QS self-defense anti-poisoning system. These findings also challenge the current hierarchical regulation model of P. aeruginosa QS systems by revealing new interconnections between them that suggest a circular model. Moreover, they uncover a novel role for MvfR in self-defense that favors antibiotic tolerance and cell survival, further demonstrating MvfR as a highly desirable anti-virulence target.
Highlights
Pseudomonas aeruginosa is a major nosocomial pathogen representing a critical threat for human health[1,2] because of its tolerance and rapid development of resistance towards almost all current antimicrobial therapies[3,4,5,6,7]
We previously described the importance of Multiple Virulence Factor Regulator (MvfR) in antibiotic tolerance[6,43,70], and here we asked whether the detoxification abilities of AhpC, AhpF, TrxB2, AhpB and Dps may contribute to this phenomenon
This study provides novel insights in the understanding of MvfR role in the complex regulation of quorum sensing (QS) and pathogenesis in P. aeruginosa
Summary
Pseudomonas aeruginosa is a major nosocomial pathogen representing a critical threat for human health[1,2] because of its tolerance and rapid development of resistance towards almost all current antimicrobial therapies[3,4,5,6,7]. On the other hand LasR positively regulates MvfR, as it binds and induces mvfR expression during exponential phase[27,35], with MvfR eventually becoming LasR-independent at the later stages of growth[35] Another interconnection between the LasR and MvfR systems is that MvfR, via the pqs operon, controls the synthesis of the precursors of PQS and of the programmed cell death signal 2-n-heptyl-4 -hydroxyquinoline-N-Oxide (HQNO)[13], while LasR controls the enzymatic conversion of their precursors into these molecules by controlling the expression of pqsH and pqsL genes respectively[26,37,48]. This work provides novel insights into the quorum sensing circuits in P. aeruginosa that are crucial for both pathogenesis and cell survival in deleterious environments, and its interconnection to the other P. aeruginosa QS systems, as well as its role in self-defense response that favors antibiotic tolerance
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