Indefinite. Restriction lift date: 10000-01-01
Molecular analysis of inflammatory mechanisms associated with Escherichia coli and inflammatory bowel diseases
| dc.check.date | 10000-01-01 | |
| dc.check.embargoformat | Both hard copy thesis and e-thesis | en |
| dc.check.entireThesis | Entire Thesis Restricted | |
| dc.check.info | Indefinite | en |
| dc.check.opt-out | Yes | en |
| dc.check.reason | This thesis is due for publication or the author is actively seeking to publish this material | en |
| dc.contributor.advisor | Melgar, Silvia | en |
| dc.contributor.advisor | Shanahan, Fergus | en |
| dc.contributor.advisor | Nally, Kenneth | en |
| dc.contributor.author | Darby, Trevor | |
| dc.contributor.funder | Science Foundation Ireland | en |
| dc.date.accessioned | 2015-06-02T11:00:21Z | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014 | |
| dc.description.abstract | Inflammatory bowel diseases (IBD), encompasses a range of chronic, immune-mediated inflammatory disorders that are usually classified under two major relapsing conditions, Crohn’s Disease (CD) and ulcerative colitis (UC). Extensive studies in the last decades have suggested that the etiology of IBD involves environmental and genetic factors that lead to dysfunction of epithelial barrier with consequent deregulation of the mucosal immune system and inadequate responses to gut microbiota.Over the last decade, the microbial species that has attracted the most attention, with respect to CD etiology, is Eschericia coli. In CD tissue, E. coli antigens have also been identified in macrophages within the lamina propria, granulomas, and in the germinal centres of mesenteric lymph nodes of patients. They have been shown to adhere to and invade intestinal epithelial cells whilst also being able to extensively replicate within macrophages. Through the work of genome-wide association studies (GWAS), there is growing evidence to suggest that the microbial imbalance between commensal and pathogenic bacteria in the gut is aided by a defect in the innate immune system. Autophagy represents a recently investigated pathway that is believed to contribute to the pathogenesis of CD, with studies identified a variant of the autophagy gene, ATG16L1, as a susceptibility gene. The aim of my thesis was to study the cellular and molecular mechanism promoted by E.coli strains in epithelial cells and to assess their contribution to IBD pathology. To achieve this we focused on developing both an in vitro and in vivo model of AIEC infection. This allowed us to further our knowledge on possible mechanisms utilised by AIEC that promoted their survival, as well as developing a better understanding of host reactions. We demonstrate a new survival mechanism promoted by E.coli HM605, whereby it induces the expression of the anti-apoptotic proteins Bcl-XL and BCL2, all of which is exacerbated in an autophagy deficient system. We have also demonstrated the presence of AIEC-induced inflammasome responses in epithelial cells which are exacerbated in an autophagy deficient system and expression of NOD-like receptors (NLRs) which might mediate inflammasome responses in vivo. Finally, we used the Citrobacter rodentium model of infectious colitis to identify Pellino3 as an important mediator in the NOD2 pathway and regulator of intestinal inflammation. In summary, we have developed robust and versatile models of AIEC infection as well as provide new insights into AIEC mediated survival pathways. The collected data provides a new perception into why AIEC bacteria are able to prosper in conditions associated with Crohn’s disease patients with a defect in autophagy. | en |
| dc.description.status | Not peer reviewed | en |
| dc.description.version | Accepted Version | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Darby, T. 2014. Molecular analysis of inflammatory mechanisms associated with Escherichia coli and inflammatory bowel diseases. PhD Thesis, University College Cork. | en |
| dc.identifier.uri | https://hdl.handle.net/10468/1830 | |
| dc.language.iso | en | en |
| dc.publisher | University College Cork | en |
| dc.rights | © 2014, Trevor Darby. | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
| dc.subject | Molecular | en |
| dc.subject | Escherichia coli | en |
| dc.subject | Crohn's disease | en |
| dc.subject | Inflammatory bowel disease | en |
| dc.thesis.opt-out | true | |
| dc.title | Molecular analysis of inflammatory mechanisms associated with Escherichia coli and inflammatory bowel diseases | en |
| dc.type | Doctoral thesis | en |
| dc.type.qualificationlevel | Doctoral | en |
| dc.type.qualificationname | PhD (Science) | en |
