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Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa
In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence funct...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040856/ https://www.ncbi.nlm.nih.gov/pubmed/35471121 http://dx.doi.org/10.1128/msystems.00113-22 |
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author | Asfahl, Kyle L. Smalley, Nicole E. Chang, Alexandria P. Dandekar, Ajai A. |
author_facet | Asfahl, Kyle L. Smalley, Nicole E. Chang, Alexandria P. Dandekar, Ajai A. |
author_sort | Asfahl, Kyle L. |
collection | PubMed |
description | In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested in determining whether there were reproducible genetic characteristics of these isolates and whether there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las- to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infections and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understand QS beyond what has been described in laboratory strains. IMPORTANCE The bacterial pathogen Pseudomonas aeruginosa can cause chronic infections that are resistant to treatment in immunocompromised individuals. Over the course of these infections, the original infecting organism adapts to the host environment. P. aeruginosa uses a cell-cell signaling mechanism termed quorum sensing (QS) to regulate virulence factors and cooperative behaviors. The key QS regulator in laboratory strains, LasR, is frequently mutated in infection-adapted isolates, leaving another transcription factor, RhlR, in control of QS gene regulation. Such isolates provide an opportunity to understand Rhl-QS regulation without the confounding effects of LasR, as well as the scope of QS in the context of within-host evolution. We show that a core group of virulence genes is regulated by RhlR in a variety of infection-adapted LasR-null isolates. Our results reveal commonalities in infection-adapted QS gene regulation and key QS factors that may serve as therapeutic targets in the future. |
format | Online Article Text |
id | pubmed-9040856 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-90408562022-04-27 Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa Asfahl, Kyle L. Smalley, Nicole E. Chang, Alexandria P. Dandekar, Ajai A. mSystems Research Article In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested in determining whether there were reproducible genetic characteristics of these isolates and whether there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las- to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infections and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understand QS beyond what has been described in laboratory strains. IMPORTANCE The bacterial pathogen Pseudomonas aeruginosa can cause chronic infections that are resistant to treatment in immunocompromised individuals. Over the course of these infections, the original infecting organism adapts to the host environment. P. aeruginosa uses a cell-cell signaling mechanism termed quorum sensing (QS) to regulate virulence factors and cooperative behaviors. The key QS regulator in laboratory strains, LasR, is frequently mutated in infection-adapted isolates, leaving another transcription factor, RhlR, in control of QS gene regulation. Such isolates provide an opportunity to understand Rhl-QS regulation without the confounding effects of LasR, as well as the scope of QS in the context of within-host evolution. We show that a core group of virulence genes is regulated by RhlR in a variety of infection-adapted LasR-null isolates. Our results reveal commonalities in infection-adapted QS gene regulation and key QS factors that may serve as therapeutic targets in the future. American Society for Microbiology 2022-04-11 /pmc/articles/PMC9040856/ /pubmed/35471121 http://dx.doi.org/10.1128/msystems.00113-22 Text en Copyright © 2022 Asfahl et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Asfahl, Kyle L. Smalley, Nicole E. Chang, Alexandria P. Dandekar, Ajai A. Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title | Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title_full | Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title_fullStr | Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title_full_unstemmed | Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title_short | Genetic and Transcriptomic Characteristics of RhlR-Dependent Quorum Sensing in Cystic Fibrosis Isolates of Pseudomonas aeruginosa |
title_sort | genetic and transcriptomic characteristics of rhlr-dependent quorum sensing in cystic fibrosis isolates of pseudomonas aeruginosa |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040856/ https://www.ncbi.nlm.nih.gov/pubmed/35471121 http://dx.doi.org/10.1128/msystems.00113-22 |
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