Investigation of the mechanisms underpinning interaction of Bifidobacterium breve with the host

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dc.check.entireThesisEntire Thesis Restricted
dc.check.infoRestricted to everyone for ten yearsen
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorNally, Kenen
dc.contributor.advisorvan Sinderen, Douween
dc.contributor.advisorShanahan, Fergusen
dc.contributor.authorHickey, Ana Claire
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderAPC Microbiome Irelanden
dc.date.accessioned2020-01-10T12:40:35Z
dc.date.available2020-01-10T12:40:35Z
dc.date.issued2019
dc.date.submitted2019
dc.description.abstractBifidobacteria are one of the first bacterial genera to colonise the gastrointestinal tract of human infants, are found in breast milk, are reported to influence immunity and to affect susceptibility to infectious and inflammatory disease as reviewed in Chapter I. However, the mechanisms through which specific Bifidobacterial microbe associated molecular patterns (MAMPs) and their corresponding host pattern recognition receptors (PRRs) influence the immune system is unclear. The aims of this thesis were to investigate how sortase dependent pili (SDP) and exopolysaccharide (EPS) alter host responses to Bifidobacterium breve. In Chapter II we used SDP expression mutants of B. breve UCC2003 to see if the presence of the pili impacted macrophage, monocyte and epithelial cell responses to the bacteria and if they impacted colonisation of the bacteria in vivo. We found that SDP did not alter macrophage or monocyte cytokine responses and that host responses to the wild type and mutant B. breve UCC2003 strains were TLR2- and MyD88-dependent. Expression of SDP allowed better adhesion of the bacteria to epithelial cells and altered chemokine responses, however, the mutants did not colonise the gastrointestinal tract of microbiota-depleted mice while the wild type strain did. Overall, we showed that while SDP expression by B. breve UCC2003 altered epithelial responses in vitro, they were disadvantageous to in vivo colonisation. In Chapter III we investigated how EPS impacted immune responses to different human B. breve isolates. From a panel of strains we found heterogeneity in EPS production and that monocyte cytokine responses did not correlate with EPS status. Focus on B. breve UCC2003 and JCM7017 and their isogenic EPSneg mutants showed that EPS altered macrophage cytokine responses differently for the two strains but reduced the amount of T cell activation by dendritic cells (DCs) to both strains. Gene expression analysis of macrophages and DCs cultured with the bacteria indicated specific differences between the two strains and the effect of EPS on both. Chapter IV investigated how this work translated in vivo. We found that neither B. breve strain was able to colonise conventionally raised C57BL/6 mice. Depletion of the microbiota with an antibiotic cocktail facilitated colonisation and systemic dissemination of B. breve UCC2003, but not that of its EPSneg mutant nor of B. breve JCM7017. Detailed investigation of the host cell type responsible for trafficking B. breve UCC2003 showed that CD103+ CD11c+ DCs contained the bacteria in a number of systemic tissues and may therefore be the cells that carry the bacteria from the gut. Overall this work highlights that B. breve UCC2003 utilises EPS but not SDP to mediate its effects on the host and that this is strain-specific.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationHickey, A. C. 2019. Investigation of the mechanisms underpinning interaction of Bifidobacterium breve with the host. PhD Thesis, University College Cork.en
dc.identifier.endpage265en
dc.identifier.urihttps://hdl.handle.net/10468/9486
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2019, Ana Claire Hickey.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectBifidobacterium breveen
dc.subjectHost responseen
dc.subjectMicrobiotaen
dc.subjectImmune responseen
dc.subjectExopolysaccharideen
dc.subjectSortase dependent pilien
dc.thesis.opt-outfalse
dc.titleInvestigation of the mechanisms underpinning interaction of Bifidobacterium breve with the hosten
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhDen
ucc.workflow.supervisork.nally@ucc.ie
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