Affecting Pseudomonas aeruginosa Phenotypic Plasticity by Quorum Sensing Dysregulation Hampers Pathogenicity in Murine Chronic Lung Infection

Abstract

In Pseudomonas aeruginosa quorum sensing (QS) activates the production of virulence factors, playing a critical role in pathogenesis. Multiple negative regulators modulate the timing and the extent of the QS response either in the pre-quorum or post-quorum phases of growth. This regulation likely increases P. aeruginosa phenotypic plasticity and population fitness, facilitating colonization of challenging environments such as higher organisms. Accordingly, in addition to the factors required for QS signals synthesis and response, also QS regulators have been proposed as targets for anti-virulence therapies. However, while it is known that P. aeruginosa mutants impaired in QS are attenuated in their pathogenic potential, the effect of mutations causing a dysregulated timing and/or magnitude of the QS response has been poorly investigated so far in animal models of infection. In order to investigate the impact of QS dysregulation on P. aeruginosa pathogenesis in a murine model of lung infection, the QteE and RsaL proteins have been selected as representatives of negative regulators controlling P. aeruginosa QS in the pre- and post-quorum periods, respectively. Results showed that the qteE mutation does not affect P. aeruginosa lethality and ability to establish chronic infection in mice, despite causing a premature QS response and enhanced virulence factors production in test tube cultures compared to the wild type. Conversely, the post-quorum dysregulation caused by the rsaL mutation hampers the establishment of P. aeruginosa chronic lung infection in mice without affecting the mortality rate. On the whole, this study contributes to a better understanding of the impact of QS regulation on P. aeruginosa phenotypic plasticity during the infection process. Possible fallouts of these findings in the anti-virulence therapy field are also discussed.

Two rsaM Homologues Encode Central Regulatory Elements Modulating Quorum Sensing in Burkholderia thailandensis

“…This could be necessary to modulate the QS response depending on specific environmental conditions, as previously suggested for other negative regulators of QS. For instance, the QteE and RsaL repressors in the human opportunistic pathogen Pseudomonas aeruginosa modulate the timing and extent of the QS response and likely increase P. aeruginosa phenotypic plasticity and population fitness, ultimately facilitating the colonization of challenging environments, including higher organisms (22,(28)(29)(30)(31)(32)(33). The RsaL protein is also found ubiquitously in the group of nonpathogenic plant-associated nitrogen-fixing Burkholderia spp., such as Burkholderia kururiensis, and its role is hypothesized to be a switch to turn on/off the AHL signaling system under various environmental conditions (22,34).…”

Characterization of the multiple molecular mechanisms underlying RsaL control of phenazine‐1‐carboxylic acid biosynthesis in the rhizosphere bacterium Pseudomonas aeruginosa PA1201

“…As a consequence, rsaL mutation in P. aeruginosa PAO1 leads to enhanced surface motility and the production of secreted virulence factors such as elastase, hemolysins, hydrogen cyanide, and PYO. Conversely, when compared with the wild type strain, the rsaL mutation decreases the ability of this pathogen to cause chronic lung infections in mice (de Kievit et al, 1999;Rampioni et al, 2009;Bond ı et al, 2014). Notably, transcriptomic analyses revealed that RsaL has a negative impact on the expression of multiple genes, including the phz1 cluster, phzM and phzS (Rampioni et al, 2007b).…”

Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR of Pseudomonas aeruginosa: Insights from molecular docking and dynamics simulations

“…It should be noted that the LasR quorum-sensing system of P. aeruginosa is regulated by prequorum and post-quorum regulating systems 86 . The first system is controlled by post-translational repressors QscR, QslA and QteE 20, [86][87][88][89] . In the absence of 3OC12-HSL, they can each form a heterodimer with LasR.…”

“…All these interactions indirectly change the conformation of the DBD, thus allosterically preventing DNA binding. It was previously shown that QslA can bind to LasR and thereby inhibit its DNA-binding capability 86 . Moreover, it has been shown that QslA supresses formation of the LasR homodimer complex by occupying the same surface area that is used for dimerization 88,89 .…”