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

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dc.contributor.advisor Gahan, Cormac G. en
dc.contributor.advisor Hill, Colin en Nolan, James A. 2015-11-04T11:22:28Z 2015-11-04T11:22:28Z 2014 2014
dc.identifier.citation Nolan, J.A. 2014. The relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactions. PhD Thesis, University College Cork. en
dc.identifier.endpage 268
dc.description.abstract This 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.sponsorship Irish Research Council for Science Engineering and Technology (EMBARK initiative); Science Foundation Ireland (Alimentary Pharmabiotic Centre SFI/12/RC/2273) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, James A. Nolan. en
dc.rights.uri en
dc.subject Listeria monocytogenes EGDe en
dc.subject HMG-CoA synthase en
dc.subject HMBPP en
dc.subject THP-1 en
dc.subject Statin en
dc.subject Rosuvastatin en
dc.subject Isoprenoid en
dc.subject Microbiota en
dc.subject Bile acid en
dc.subject Inflammation en
dc.subject Non-essential en
dc.subject Immunity en
dc.subject Antigen presentation en
dc.title The relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactions en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en Microbiology en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Spring Conferring 2015

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© 2014, James A. Nolan. Except where otherwise noted, this item's license is described as © 2014, James A. Nolan.
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