Characterization of lasR-deficient clinical isolates of Pseudomonas aeruginosa

Wang, Yao; Gao, Leiqiong; Rao, Xiancai; Wang, Jing; Yu, Hua; Jiang, Junru; Zhou, Wei; Wang, Jin; Xiao, Yonghong; Li, Mengwen; Zhang, Yan; Zhang, Kebin; Shen, Li; Zeng, Hua

doi:10.1038/s41598-018-30813-y

Cited by 50 publications

(50 citation statements)

References 55 publications

(71 reference statements)

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“…These conditions also lead to an increase in mutations in the QS transcriptional regulator-encoding gene lasR. As lasR deletion strains grow to higher cell densities and have higher denitrification rates, it has been suspected that these mutations increase the fitness of the population during infection [44][45][46].…”

Section: The Crp/fnr and Ctra/qs Regulons Overlap In Dinoroseobacter mentioning

confidence: 99%

Interactions among Redox Regulators and the CtrA Phosphorelay in Dinoroseobacter shibae and Rhodobacter capsulatus

Koppenhöfer

Lang

2020

Microorganisms

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Bacteria employ regulatory networks to detect environmental signals and respond appropriately, often by adjusting gene expression. Some regulatory networks influence many genes, and many genes are affected by multiple regulatory networks. Here, we investigate the extent to which regulatory systems controlling aerobic–anaerobic energetics overlap with the CtrA phosphorelay, an important system that controls a variety of behavioral processes, in two metabolically versatile alphaproteobacteria, Dinoroseobacter shibae and Rhodobacter capsulatus. We analyzed ten available transcriptomic datasets from relevant regulator deletion strains and environmental changes. We found that in D. shibae, the CtrA phosphorelay represses three of the four aerobic–anaerobic Crp/Fnr superfamily regulator-encoding genes (fnrL, dnrD, and especially dnrF). At the same time, all four Crp/Fnr regulators repress all three phosphorelay genes. Loss of dnrD or dnrF resulted in activation of the entire examined CtrA regulon, regardless of oxygen tension. In R. capsulatus FnrL, in silico and ChIP-seq data also suggested regulation of the CtrA regulon, but it was only with loss of the redox regulator RegA where an actual transcriptional effect on the CtrA regulon was observed. For the first time, we show that there are complex interactions between redox regulators and the CtrA phosphorelays in these bacteria and we present several models for how these interactions might occur.

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Section: The Crp/fnr and Ctra/qs Regulons Overlap In Dinoroseobacter mentioning

confidence: 99%

Interactions among Redox Regulators and the CtrA Phosphorelay in Dinoroseobacter shibae and Rhodobacter capsulatus

Koppenhöfer

Lang

2020

Microorganisms

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“…We are interested in the regulatory remodeling of QS that occurs in isolates of P. aeruginosa from chronic infections, including those in CF. To begin to understand how RhlR-mediated QS in clinical isolates might be different from that of laboratory strains[15,16,18,19], we studied a CF isolate called E90[20], which contains a single base-pair deletion in lasR at base 170, and uses RhlR to mediate QS. E90 produces QS-regulated virulence factors at levels comparable to that of PAO1.…”

Section: Introductionmentioning

confidence: 99%

Non-hierarchical, RhlR-regulated acyl-homoserine lactone quorum sensing in a cystic fibrosis isolate ofPseudomonas aeruginosa

Cruz

Asfahl

Bossche

et al. 2019

Preprint

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2 The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in 3 cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and 4 interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors 5 such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this 6 hierarchy, and activates the transcription of dozens of genes, including that encoding the QS 7 regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from 8 CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have 9 recently shown that in CF isolates, the QS circuitry is often "rewired" such that RhlR acts in a 10 LasR-independent manner. To begin understanding how QS activity differs in this "rewired" 11 background, we characterized QS activation and RhlR-regulated gene expression in P.12 aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates 13 the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR 14 include several that encode virulence factors. Some, but not all, of these genes are present in the 15 QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 16 produces virulence factors at similar concentrations to that of PAO1. Unlike PAO1, cytotoxicity by 17 E90 in a three-dimensional lung epithelium cell model is also RhlR-regulated. These data 18 illuminate a "rewired" LasR-independent RhlR regulon in chronic infection isolates and suggest 19 that RhlR may be a target for therapeutic development in chronic infections. 2 20 AUTHOR SUMMARY 21 Pseudomonas aeruginosa is a prominent cystic fibrosis (CF) pathogen that uses quorum sensing 22 (QS) to regulate virulence. In laboratory strains, the key QS regulator is LasR. Some isolates from 23 patients with chronic CF infections appear to use an alternate QS circuitry in which another 24 transcriptional regulator, RhlR, mediates QS. We show that a LasR-null CF clinical isolate 25 engages in QS through RhlR and remains capable of inducing cell death in an in vivo-like lung 26 epithelium cell model. Our findings support the notion that LasR-null clinical isolates can engage 27 in RhlR QS and highlight the centrality of RhlR gene regulation in chronic P. aeruginosa infections. 3 28 INTRODUCTION 29 Many species of bacteria are able to sense and communicate with each other via quorum sensing 30 (QS), a cell-density dependent gene regulation mechanism[1]. In Proteobacteria, acyl-31 homoserine lactones (HSL) are used as QS signals. Commonly, signals are produced by acyl-32 HSL synthases of the luxI family and are recognized by their cognate receptors, transcription 33 factors of the luxR family[2].34 35 Pseudomonas aeruginosa, a leading cause of airway infection in cystic fibrosis (CF) patients, 36 uses QS to regulate the production of a wide array of virulence factors including phenazines, 3...

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“…We are interested in the regulatory remodeling of QS that occurs in isolates of P. aeruginosa from chronic infections, including those in CF. To begin to understand how RhlR-mediated QS in clinical isolates might be different from that in laboratory strains (15,16,18,20), we studied a CF isolate called E90 (21), which contains a single-base-pair deletion in lasR at base 170, and uses RhlR to mediate QS. E90 produces QS-regulated virulence factors at levels comparable to those of PAO1.…”

mentioning

confidence: 99%

RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of Pseudomonas aeruginosa

Cruz

Asfahl

Bossche

et al. 2020

mBio

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The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy and activates the transcription of dozens of genes, including that encoding the QS regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have recently shown that in CF isolates, the QS circuitry is often rewired such that RhlR acts in a LasR-independent manner. To begin understanding how QS activity differs in this rewired background, we characterized QS activation and RhlR-regulated gene expression in P. aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR include several that encode virulence factors. Some, but not all, of these genes are present in the QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 produces virulence factors at similar concentrations as PAO1, and in E90, RhlR plays a significant role in mediating cytotoxicity in a three-dimensional lung epithelium cell model. These data illuminate a rewired LasR-independent RhlR regulon in chronic infection isolates and suggest further investigation of RhlR as a possible target for therapeutic development in chronic infections. IMPORTANCE Pseudomonas aeruginosa is a prominent cystic fibrosis (CF) pathogen that uses quorum sensing (QS) to regulate virulence. In laboratory strains, the key QS regulator is LasR. Many isolates from patients with chronic CF infections appear to use an alternate QS circuitry in which another transcriptional regulator, RhlR, mediates QS. We show that a LasR-null CF clinical isolate engages in QS through RhlR and remains capable of inducing cell death in an in vivo-like lung epithelium cell model. Our findings support the notion that LasR-null clinical isolates can engage in RhlR QS and highlight the centrality of RhlR in chronic P. aeruginosa infections.

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Characterization of lasR-deficient clinical isolates of Pseudomonas aeruginosa

Cited by 50 publications

References 55 publications

Interactions among Redox Regulators and the CtrA Phosphorelay in Dinoroseobacter shibae and Rhodobacter capsulatus

Interactions among Redox Regulators and the CtrA Phosphorelay in Dinoroseobacter shibae and Rhodobacter capsulatus

Non-hierarchical, RhlR-regulated acyl-homoserine lactone quorum sensing in a cystic fibrosis isolate ofPseudomonas aeruginosa

RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of Pseudomonas aeruginosa

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