Flagellin is a highly immunogenic, bacterial protein considered to be abundant in the intestinal lumen. It has been reported to be an immunodominant antigen in patients with inflammatory bowel disease (IBD). In the work presented in this thesis several complementary murine models of IBD were employed to elucidate the role of innate immune sensing of flagellin in the development of intestinal inflammation. Pattern recognition receptors (PRRs) enable mammals to discriminate self from non-self through the recognition of microbial signatures, such as bacterial flagellin. Flagellin is detected by at least two distinct PRRs, NOD-like receptor 4 (NLRC4) and Toll-like receptor 5 (TLR5). Our experiments revealed that NLRC4 promoted protective effects during acute intestinal inflammation mediated by infection with Citrobacter rodentium, a close relative of enteropathogenic E. coli. Following infection with C. rodentium, Nlrc4<sup>-/-</sup> mice developed more severe weight loss, increased bacterial colonisation levels and exacerbated intestinal inflammation compared to WT counterparts. Bone marrow chimera experiments revealed that NLRC4 expression in non-hematopoietic cells provided protection and intestinal epithelial cells expressed high NLRC4 mRNA levels. These results suggest that NLRC4 inflammasome activation in the intestinal epithelium provides potent, protective effects during infection with a mucosal pathogen. In contrast, TLR5 was shown to promote protective effects during chronic, T-cell mediated intestinal inflammation driven by adoptive transfer of naïve CD4+ T-cells into lymphopenic Rag<sup>-/-</sup> hosts. The absence of TLR5 in Rag<sup>-/-</sup> recipients resulted in accelerated and exacerbated IBD. Furthermore, chronic T-cell dependent colitis driven by Helicobacter hepaticus, a flagellated, enteric bacterium, was more severe in mice deficient in TLR5. Finally, construction of a H.hepaticus Type 6 secretion system deletion mutant revealed delayed pathogenicity in an innate model of intestinal inflammation, most likely due to reduced initial colonisation of mutant H.hepaticus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647535 |
| Date | January 2013 |
| Creators | Nordlander, Sofia |
| Contributors | Maloy, Kevin J. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:775c4150-9b22-4008-9288-3a6053cbf4cc |
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