Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers

ABSTRACT The Steroids for Corneal Ulcers Trial (SCUT) was a multicenter, international study of bacterial keratitis in which 101 Pseudomonas aeruginosa infections were treated. Twenty-two of 101 P. aeruginosa isolates collected had a colony morphology characteristic of a loss-of-function mutation in...

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Autores principales:	John H. Hammond, Wesley P. Hebert, Amanda Naimie, Kathryn Ray, Rachel D. Van Gelder, Antonio DiGiandomenico, Prajna Lalitha, Muthiah Srinivasan, Nisha R. Acharya, Thomas Lietman, Deborah A. Hogan, Michael E. Zegans
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Anr bacterial keratitis corneal ulcer CupA eye infection LasR Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a468f1dcf82c4c53beb31271c81f3647
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spelling	oai:doaj.org-article:a468f1dcf82c4c53beb31271c81f36472021-11-15T15:21:30ZEnvironmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers10.1128/mSphere.00140-162379-5042https://doaj.org/article/a468f1dcf82c4c53beb31271c81f36472016-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00140-16https://doaj.org/toc/2379-5042ABSTRACT The Steroids for Corneal Ulcers Trial (SCUT) was a multicenter, international study of bacterial keratitis in which 101 Pseudomonas aeruginosa infections were treated. Twenty-two of 101 P. aeruginosa isolates collected had a colony morphology characteristic of a loss-of-function mutation in lasR, the gene encoding a quorum-sensing master regulator. Ulcers caused by these 22 strains were associated with larger areas of corneal opacification, worse vision, and a lower rate of vision recovery in response to treatment than ulcers caused by the other isolates. The lasR sequences from these isolates each contained one of three nonsynonymous substitutions, and these strains were deficient in production of LasR-regulated protease and rhamnolipids. Replacement of lasR with either of the two most common lasR alleles from the SCUT isolates was sufficient to decrease protease and rhamnolipid production in PA14. Loss of LasR function is associated with increased production of CupA fimbriae, and the LasR-defective isolates exhibited higher production of CupA fimbriae than LasR-intact isolates. Strains with the same lasR mutation were of the same multilocus sequence type, suggesting that LasR-deficient, environmental P. aeruginosa strains were endemic to the area, and infections caused by these strains were associated with worse patient outcomes in the SCUT study. (This study has been registered at ClinicalTrials.gov under registration no. NCT00324168 .) IMPORTANCE The LasR transcription factor is an important regulator of quorum sensing in P. aeruginosa and positively controls multiple virulence-associated pathways. The emergence of strains with lasR loss-of-function alleles in chronic disease is well described and is thought to represent a specific adaptation to the host environment. However, the prevalence and virulence of these strains in acute infections remain unclear. This report describes observations revealing that lasR mutants were common among isolates from a large, multicenter clinical study of keratitis and were associated with worse clinical outcomes than LasR-intact strains despite reduced production of LasR-regulated factors. Additionally, these lasR mutants were closely related strains or clones, as determined by molecular analysis. Because bacterial keratitis is community acquired, these data indicate infection by endemic, LasR-deficient strains in the environment. These results suggest that the conventional paradigm regarding the role for LasR-mediated regulation of virulence is more complex than previously appreciated.John H. HammondWesley P. HebertAmanda NaimieKathryn RayRachel D. Van GelderAntonio DiGiandomenicoPrajna LalithaMuthiah SrinivasanNisha R. AcharyaThomas LietmanDeborah A. HoganMichael E. ZegansAmerican Society for MicrobiologyarticleAnrbacterial keratitiscorneal ulcerCupAeye infectionLasRMicrobiologyQR1-502ENmSphere, Vol 1, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Anr bacterial keratitis corneal ulcer CupA eye infection LasR Microbiology QR1-502
spellingShingle	Anr bacterial keratitis corneal ulcer CupA eye infection LasR Microbiology QR1-502 John H. Hammond Wesley P. Hebert Amanda Naimie Kathryn Ray Rachel D. Van Gelder Antonio DiGiandomenico Prajna Lalitha Muthiah Srinivasan Nisha R. Acharya Thomas Lietman Deborah A. Hogan Michael E. Zegans Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
description	ABSTRACT The Steroids for Corneal Ulcers Trial (SCUT) was a multicenter, international study of bacterial keratitis in which 101 Pseudomonas aeruginosa infections were treated. Twenty-two of 101 P. aeruginosa isolates collected had a colony morphology characteristic of a loss-of-function mutation in lasR, the gene encoding a quorum-sensing master regulator. Ulcers caused by these 22 strains were associated with larger areas of corneal opacification, worse vision, and a lower rate of vision recovery in response to treatment than ulcers caused by the other isolates. The lasR sequences from these isolates each contained one of three nonsynonymous substitutions, and these strains were deficient in production of LasR-regulated protease and rhamnolipids. Replacement of lasR with either of the two most common lasR alleles from the SCUT isolates was sufficient to decrease protease and rhamnolipid production in PA14. Loss of LasR function is associated with increased production of CupA fimbriae, and the LasR-defective isolates exhibited higher production of CupA fimbriae than LasR-intact isolates. Strains with the same lasR mutation were of the same multilocus sequence type, suggesting that LasR-deficient, environmental P. aeruginosa strains were endemic to the area, and infections caused by these strains were associated with worse patient outcomes in the SCUT study. (This study has been registered at ClinicalTrials.gov under registration no. NCT00324168 .) IMPORTANCE The LasR transcription factor is an important regulator of quorum sensing in P. aeruginosa and positively controls multiple virulence-associated pathways. The emergence of strains with lasR loss-of-function alleles in chronic disease is well described and is thought to represent a specific adaptation to the host environment. However, the prevalence and virulence of these strains in acute infections remain unclear. This report describes observations revealing that lasR mutants were common among isolates from a large, multicenter clinical study of keratitis and were associated with worse clinical outcomes than LasR-intact strains despite reduced production of LasR-regulated factors. Additionally, these lasR mutants were closely related strains or clones, as determined by molecular analysis. Because bacterial keratitis is community acquired, these data indicate infection by endemic, LasR-deficient strains in the environment. These results suggest that the conventional paradigm regarding the role for LasR-mediated regulation of virulence is more complex than previously appreciated.
format	article
author	John H. Hammond Wesley P. Hebert Amanda Naimie Kathryn Ray Rachel D. Van Gelder Antonio DiGiandomenico Prajna Lalitha Muthiah Srinivasan Nisha R. Acharya Thomas Lietman Deborah A. Hogan Michael E. Zegans
author_facet	John H. Hammond Wesley P. Hebert Amanda Naimie Kathryn Ray Rachel D. Van Gelder Antonio DiGiandomenico Prajna Lalitha Muthiah Srinivasan Nisha R. Acharya Thomas Lietman Deborah A. Hogan Michael E. Zegans
author_sort	John H. Hammond
title	Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
title_short	Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
title_full	Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
title_fullStr	Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
title_full_unstemmed	Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers
title_sort	environmentally endemic <named-content content-type="genus-species">pseudomonas aeruginosa</named-content> strains with mutations in <italic toggle="yes">lasr</italic> are associated with increased disease severity in corneal ulcers
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/a468f1dcf82c4c53beb31271c81f3647
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Environmentally Endemic <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Strains with Mutations in <italic toggle="yes">lasR</italic> Are Associated with Increased Disease Severity in Corneal Ulcers

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