Understanding the molecular mechanism through which aspirated bile triggers chronic Pseudomonas aeruginosa infections in respiratory disease

dc.check.embargoformatEmbargo not applicable (If you have not submitted an e-thesis or do not want to request an embargo)en
dc.check.infoNot applicableen
dc.check.opt-outNot applicableen
dc.check.reasonNot applicableen
dc.check.typeNo Embargo Required
dc.contributor.advisorO'Gara, Fergalen
dc.contributor.advisorReen, F.Jerryen
dc.contributor.authorFlynn, Stephanie
dc.contributor.funderIrish Research Council for Science, Engineering and Technologyen
dc.date.accessioned2019-08-21T12:01:40Z
dc.date.available2019-08-21T12:01:40Z
dc.date.issued2019
dc.date.submitted2019
dc.description.abstractThe opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality in Cystic Fibrosis (CF) patients. Extensive genomic adaptation of this organism facilitates its emergence as a dominant organism within the lung microbial community and to its ability to chronically persist within the CF airways. The environmental and host factors contributing to the success of this species in vivo have been the subject of intensive research efforts. Gastro-oesophageal reflux (GOR) has recently emerged as a major co-morbidity in CF and a range of other respiratory conditions and is associated with the presence of bile acids in the lungs of CF patients, a consequence of micro-aspiration of refluxed gastric contents. This thesis aimed to investigate the impact that bile exerts on the global lung microbiota and the key CF associated pathogen P. aeruginosa. The detection of bile acids in paediatric CF patients using liquid chromatography mass spectrometry (LC-MS) analysis correlated with a reduction in lung microbial biodiversity and the emergence of dominant respiratory pathogens including P. aeruginosa. Bile acids may contribute to the progressive restructuring of the lung microbiota towards a pathogen dominated state associated with worse clinical outcomes. Bile and the active component bile acids were found to be capable of triggering P. aeruginosa to transition to a chronic, antibiotic tolerant lifestyle through a combination of transcriptional and phenotypic responses. Functional screens based on biofilm formation and growth on bile identified key two component systems mediating the biofilm response to bile with a connection to central metabolism becoming apparent. The latter screen identified the glyoxylate shunt as a key breakpoint in the suppression of redox potential as part of the bile response. Bile was also found to be capable of selecting for genetic variants in an in vitro system known to mimic conditions found within the CF lung environment. Pigmented derivatives emerged exclusively in the presence of bile with genome sequencing identifying single nucleotide polymorphisms (SNPs) in quorum sensing (lasR) and both the pyocyanin (phzS) and pyomelanin (hmgA) biosynthetic pathways. These mutations have been previously described in various clinical isolates of P. aeruginosa. Loss of Pseudomonas Quinolone Signal (PQS) production in the pigmented variants underpinned the loss of redox suppression in response to bile, perhaps a consequence of the anti-oxidant/pro-oxidant activities attributed to the PQS signalling molecule. Bile is therefore capable of influencing the evolutionary trajectory of this respiratory pathogen, a key finding in understanding the emergence of genotypic and phenotypic heterogeneity within the lungs of patients with respiratory disease. Collectively, this research supports the role for bile in the progression of chronic infection in CF through its impact on P. aeruginosa and other respiratory pathogens. Therefore, the early detection and profiling of bile acids utilising rapid point of care devices could lead to the identification of high risk paediatric patients and to the development of increasingly effective intervention strategies to prevent the establishment of chronic respiratory microbiota.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFlynn, S. 2019. Understanding the molecular mechanism through which aspirated bile triggers chronic Pseudomonas aeruginosa infections in respiratory disease. PhD Thesis, University College Cork.en
dc.identifier.endpage354en
dc.identifier.urihttps://hdl.handle.net/10468/8367
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2019, Stephanie Flynn.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectPseudomonas aeruginosaen
dc.subjectBileen
dc.subjectGastrooesophageal refluxen
dc.subjectChronicen
dc.subjectAdaptationen
dc.subjectPigmenteden
dc.subjectBiofilmen
dc.subjectCystic fibrosisen
dc.thesis.opt-outfalse
dc.titleUnderstanding the molecular mechanism through which aspirated bile triggers chronic Pseudomonas aeruginosa infections in respiratory diseaseen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhDen
ucc.workflow.supervisorj.reen@ucc.ie
Files
Original bundle
Now showing 1 - 3 of 3
Loading...
Thumbnail Image
Name:
FlynnS_PhD2019 Abstract.pdf
Size:
109.21 KB
Format:
Adobe Portable Document Format
Description:
Abstract
Loading...
Thumbnail Image
Name:
FlynnS_PhD2019.docx
Size:
13.69 MB
Format:
Microsoft Word XML
Description:
Full Text E-thesis (Word)
Loading...
Thumbnail Image
Name:
FlynnS_PhD2019.pdf
Size:
9.1 MB
Format:
Adobe Portable Document Format
Description:
Full Text E-thesis
License bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
license.txt
Size:
5.62 KB
Format:
Item-specific license agreed upon to submission
Description: