Abstract
Pathogenic bacteria use interconnected multi-layered regulatory networks, such as quorum sensing (QS) networks to sense and respond to environmental cues and external and internal bacterial cell signals, and thereby adapt to and exploit target hosts. Despite the many advances that have been made in understanding QS regulation, little is known regarding how these inputs are integrated and processed in the context of multi-layered QS regulatory networks. Here we report the examination of the Pseudomonas aeruginosa QS 4-hydroxy-2-alkylquinolines (HAQs) MvfR regulatory network and determination of its interaction with the QS acyl-homoserine-lactone (AHL) RhlR network. The aim of this work was to elucidate paradigmatically the complex relationships between multi-layered regulatory QS circuitries, their signaling molecules, and the environmental cues to which they respond. Our findings revealed positive and negative homeostatic regulatory loops that fine-tune the MvfR regulon via a multi-layered dependent homeostatic regulation of the cell-cell signaling molecules PQS and HHQ, and interplay between these molecules and iron. We discovered that the MvfR regulon component PqsE is a key mediator in orchestrating this homeostatic regulation, and in establishing a connection to the QS rhlR system in cooperation with RhlR. Our results show that P. aeruginosa modulates the intensity of its virulence response, at least in part, through this multi-layered interplay. Our findings underscore the importance of the homeostatic interplay that balances competition within and between QS systems via cell-cell signaling molecules and environmental cues in the control of virulence gene expression. Elucidation of the fine-tuning of this complex relationship offers novel insights into the regulation of these systems and may inform strategies designed to limit infections caused by P. aeruginosa and related human pathogens.
Highlights
Microbes translate environmental cues to coordinate and modulate gene expression such that they can adapt to different niches and overcome hostile environments
This information can be in the form of small self-secreted molecules acting as signals to activate or inhibit the expression of genes
Our results show that this pathogen uses two highly sensitive networks, namely MvfR and LasR/RhlR pathways, to modulate its virulence functions by titrating the concentration of the small molecules HHQ and PQS in a manner that depends upon the presence or absence of iron
Summary
Microbes translate environmental cues to coordinate and modulate gene expression such that they can adapt to different niches and overcome hostile environments. Adaptation and coordination of gene expression is important for pathogenic microorganisms that need to colonize dynamic host environments since their ability to sense and respond to host environmental cues is critical for their survival. Many studies have addressed the role of quorum sensing (QS) communication networks in virulence where by diffusible intercellular auto-inducers factor and environmental signals bacterial cultures mediate pathogenicity by coordinating the expression of a large array of genes [1,2]. Less is known regarding how environmental cues are translated in the context of QS signaling and how environmental cues and QS are integrated to promote the ability of a pathogen to survive and colonize particular niches within their host environments. The processing and integration of environmental inputs in QS becomes even more complex when a pathogen is able to occupy more than one niche
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