RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

ABSTRACT 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 elast...

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Autores principales:	Renae L. Cruz, Kyle L. Asfahl, Sara Van den Bossche, Tom Coenye, Aurélie Crabbé, Ajai A. Dandekar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	chronic infection RhlR cytotoxicity transcriptome Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3cfd45f3bc1647b5bc6bf4112cef5bcb
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spelling	oai:doaj.org-article:3cfd45f3bc1647b5bc6bf4112cef5bcb2021-11-15T15:57:03ZRhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>10.1128/mBio.00532-202150-7511https://doaj.org/article/3cfd45f3bc1647b5bc6bf4112cef5bcb2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00532-20https://doaj.org/toc/2150-7511ABSTRACT 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.Renae L. CruzKyle L. AsfahlSara Van den BosscheTom CoenyeAurélie CrabbéAjai A. DandekarAmerican Society for Microbiologyarticlechronic infectionRhlRcytotoxicitytranscriptomechronic infectionMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic infection RhlR cytotoxicity transcriptome chronic infection Microbiology QR1-502
spellingShingle	chronic infection RhlR cytotoxicity transcriptome chronic infection Microbiology QR1-502 Renae L. Cruz Kyle L. Asfahl Sara Van den Bossche Tom Coenye Aurélie Crabbé Ajai A. Dandekar RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
description	ABSTRACT 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.
format	article
author	Renae L. Cruz Kyle L. Asfahl Sara Van den Bossche Tom Coenye Aurélie Crabbé Ajai A. Dandekar
author_facet	Renae L. Cruz Kyle L. Asfahl Sara Van den Bossche Tom Coenye Aurélie Crabbé Ajai A. Dandekar
author_sort	Renae L. Cruz
title	RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_short	RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full	RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_fullStr	RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full_unstemmed	RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_sort	rhlr-regulated acyl-homoserine lactone quorum sensing in a cystic fibrosis isolate of <named-content content-type="genus-species">pseudomonas aeruginosa</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3cfd45f3bc1647b5bc6bf4112cef5bcb
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RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

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