Zilbauer, M.; (2007) Innate immune defence to Campylobacter jejuni. Doctoral thesis , University of London.

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Abstract

Campylobacter jejuni is the most prevalent cause of bacterial diarrhoea worldwide and is frequently associated with severe post-infectious complications such as the Guillain-Barre syndrome. Despite the serious health burden caused by the bacterium disease pathogenesis remains ill defined. Human (3-defensins (hBDs), a family of epithelial antimicrobial peptides, are a major component of host innate defence at mucosal surfaces. In the present study we investigated the effect of C. jejuni on intestinal epithelial innate responses. Up-regulation of IL-8, hBD-2 and hBD-3 gene and peptide expression was observed in Caco-2 and HT-29 cell-lines in response to C. jejuni strains 11168H and 81-176. Furthermore, recombinant hBDs were found to exhibit potent bactericidal activity against C. jejuni suggesting a major role for these peptides in disease pathogenesis. Secondly, we aimed to identify host receptor(s) involved in sensing of C. jejuni and initiating innate defence. Given the invasive nature of infection, we investigated the potential role of cytoplasmic nucleotide-binding oligomerisation domain (NOD) proteins. Using small interfering (si) RNA targeting NODI and transfection of NOD2 overexpression plasmids, we identified NODI as a major pattern recognition receptor involved in mediating innate host defence to C. jejuni while NOD2 was found to play a minor role. Additionally, reduced NODI expression resulted in an increased number of intracellular C. jejuni thus highlighting a critical role for NODI mediated antimicrobial defence in limiting infection. In the final part of the study an ex-vivo model of C. jejuni infection using human intestinal biopsies was developed. Additionally, a vertical diffusion chamber system was utilised to improve culture conditions in C. jejuni infection models. In conclusion, this study highlights the important role of intestinal innate host defence to C. jejuni. The development of new and improved models of infections has the potential to provide previously unavailable opportunities to study C. jejuni disease pathogenesis.

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