A Genomic and Proteomic Investigation Into the Clostridium botulinum Neurotoxin Complex

Ashton, Philip Matthew (2014). A Genomic and Proteomic Investigation Into the Clostridium botulinum Neurotoxin Complex. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f036

Abstract

Clostridium botulinum and some strains of C. baratii and C. butyricum produce one of the most potent toxins known to man, botulinum neurotoxin, and are responsible for the disease botulism. This severe neuroparalytic disease is the result of botulinum neurotoxin negotiating a complex path to the cholinergic nerve endings. There, it interferes with the release of excitatory neurotransmitters resulting in flaccid paralysis and if untreated, death. The neurotoxin, itself a multi-faceted protein, does not act alone but is produced as part of a large, hetero-multimeric complex with the associated non-toxic proteins. This complex, known to protect the toxin from acids and proteases in the gut, has recently been suggested to play a more active role in toxicity. Here, the proteins from the lesser-studied toxin complex type (the OrfX type) are shown for the first time to share sequence similarity and synteny with clusters of proteins that are co-localised with various putative toxin genes in diverse other species. The extracellular supernatant proteome of C. butyricum is characterised and mined for potential novel virulence factors, with metabolic cost of extracellular protein being highlighted as a potential marker of virulence associated extracellular proteins. The supernatant of 22 clinical strains of C. butyricum were investigated for the presence of the toxin complex; all toxin complex components were identified in the majority of strains indicating the importance of these proteins in the causation of botulism. A relationship between OrfX-encoding strains and infant botulism was also uncovered in clinical strains from the UK. Hypotheses to explain this association are explored. Finally, the transcriptome of C. butyricum was investigated using RNA-sequencing. This uncovered a complex and diverse picture of transcription in C. butyricum and raised questions as to the role of the alternative sigma factor BotR in the regulation of bont.

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