Understanding the genetic mechanisms of Clostridium difficile toxin regulation and clinical relapse

Lister, Michelle M. (2018) Understanding the genetic mechanisms of Clostridium difficile toxin regulation and clinical relapse. PhD thesis, University of Nottingham.

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Abstract

Clostridium difficile is the leading cause of health care associated diarrhoea and remains a burden for the NHS. Disease symptoms can range from mild diarrhoea through to fulminant pseudomembranous colitis, resulting in mortality for some patients. Recurrence is a major problem and estimates are that 20% of all patients with disease will either relapse (with the same strain) or have a re-infection (with a different strain).

Arguably, the main virulence factors are toxins A (TcdA) and toxin B (TcdB) which cause disease symptoms. The genes encoding TcdA and TcdB are located within the pathogenicity locus (PaLoc) along with three accessory genes; tcdR, tcdE and tcdC. The regulatory network has been studied but we aimed to add to this knowledge by using two under investigated strains R20291 a so-called hypervirulent strain and VPI 10463 a strain known to produce higher levels of toxin.

Two different methods of investigation were employed during this study to improve our understanding of both the regulation of TcdA / TcdB but also the genetic mechanisms behind clinical relapse. These methods were; using forward and reverse genetic analysis to assess phenotypic differences and using bioinformatics to identify genes and / or single nucleotide variants (SNP) that may play a role.

Using a combination these methods we have identified potential regulators of toxin production in both strains. We have also identified unique genes and SNPs that might provide a fitness benefit to strains of C. difficile that were isolated from patients who had suffered relapse episodes.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Kuehne, Sarah A.
Minton, Nigel P.
Cockayne, A.
Subjects: Q Science > QH Natural history. Biology > QH426 Genetics
Q Science > QR Microbiology > QR 75 Bacteria. Cyanobacteria
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 53216
Depositing User: Lister, Michelle
Date Deposited: 13 Dec 2018 04:40
Last Modified: 08 Feb 2019 08:46
URI: http://eprints.nottingham.ac.uk/id/eprint/53216

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