The relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactions

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dc.check.embargoformatNot applicableen
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dc.contributor.advisorGahan, Cormac G.en
dc.contributor.advisorHill, Colinen
dc.contributor.authorNolan, James A.
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2015-11-04T11:22:28Z
dc.date.available2015-11-04T11:22:28Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractThis thesis was undertaken to investigate the relevance of two bacterial isoprenoid biosynthetic pathways (Mevalonate (MVAL) and 2-C-methyl-D-erythritol 4-phosphate (MEP)) for host-microbe interactions. We determined a significant reduction in microbial diversity in the murine gut microbiota (by next generation sequencing) following oral administration of a common anti-cholesterol drug Rosuvastatin (RSV) that targets mammalian and bacterial HMG-CoA reductase (HMG-R) for inhibition of MVAL formation. In tandem we identified significant hepatic and intestinal off-target alterations to the murine metabolome indicating alterations in inflammation, bile acid profiles and antimicrobial peptide synthesis with implications on community structure of the gastrointestinal microbiota in statin-treated animals. However we found no effect on local Short Chain Fatty Acid biosynthesis (metabolic health marker in our model). We demonstrated direct inhibition of bacterial growth in-vitro by RSV which correlated with reductions in bacterial MVAL formation. However this was only at high doses of RSV. Our observations demonstrate a significant RSV-associated impact on the gut microbiota prompting similar human analysis. Successful deletion of another MVAL pathway enzyme (HMG-CoA synthase (mvaS)) involved in Listeria monocytogenes EGDe isoprenoid biosynthesis determined that the enzyme is non-essential for normal growth and in-vivo pathogenesis of this pathogen. We highlight potential evidence for alternative means of synthesis of the HMG-CoA substrate that could render mvaS activity redundant under our test conditions. Finally, we showed by global gene expression analysis (Massive Analysis of cDNA Ends (MACE RNA-seq) a significant role for the penultimate MEP pathway metabolite (E)-4-hydroxy-3-methyl-2-but-2-enyl pyrophosphate (HMBPP) in significant up regulation of genes of immunity and antigen presentation in THP-1 cells at nanomolar levels. We infected THP-1 cells with wild type or HMBPP under/over-producing L. monoctyogenes EGDe mutants and determined subtle effects of HMBPP upon overall host responses to Listeria infection. Overall our findings provide greater insights regarding bacterial isoprenoid biosynthetic pathways for host-microbe/microbe-host dialogue.en
dc.description.sponsorshipIrish Research Council for Science Engineering and Technology (EMBARK initiative); Science Foundation Ireland (Alimentary Pharmabiotic Centre SFI/12/RC/2273)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationNolan, J.A. 2014. The relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactions. PhD Thesis, University College Cork.en
dc.identifier.endpage268
dc.identifier.urihttps://hdl.handle.net/10468/2023
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, James A. Nolan.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectListeria monocytogenes EGDeen
dc.subjectHMG-CoA synthaseen
dc.subjectHMBPPen
dc.subjectTHP-1en
dc.subjectStatinen
dc.subjectRosuvastatinen
dc.subjectIsoprenoiden
dc.subjectMicrobiotaen
dc.subjectBile aciden
dc.subjectInflammationen
dc.subjectNon-essentialen
dc.subjectImmunityen
dc.subjectAntigen presentationen
dc.thesis.opt-outfalse
dc.titleThe relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactionsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisorc.gahan@ucc.ie
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