Determinants of vacuolating cytotoxin production and its impact on Helicobacter pylori pathogenesis
Masters, Charlotte Grace (2010) Determinants of vacuolating cytotoxin production and its impact on Helicobacter pylori pathogenesis. PhD thesis, University of Nottingham.
Introduction: The vacuolating cytotoxin is an important H. pylori virulence factor and is naturally polymorphic, one of the most diverse regions being the signal region (type s1 or s2). Signal type determines vacuolating activity: type s1 strains are vacuolating and are associated with peptic ulcers and gastric adenocarcinoma; and type s2 strains are non-vacuolating. Heterogeneity in VacA levels between strains also exists, and different strains produce different amounts: this is due to differences in vacA transcription and differences in protein secretion between strains. A vacA promoter and a transcriptional start point (TSP) have been identified. Sequence analysis revealed that -35 and -10 motifs are well conserved. Mutagenesis of this region resulted in a decrease in vacA transcription in vitro. However, investigation of vacA expression between 8 different H. pylori strains using real-time PCR revealed that differences in vacA transcription observed between different strains were unrelated to the putative -35 and -10 motifs. VacA type s1 and s2 signal sequences differ in the cleavage recognition site at key positions. In type s1 the more favourable serine and proline residues are at positions -3 and -6 respectively, whereas type s2 strains have leucine present at -3 and glycine at -6. In addition to VacA type, the determinants of VacA production are of importance in H. pylori pathogenesis: It has been shown that larger amounts of toxin produce greater damage in animal models. However there is limited information on the level of vacA expression in vivo and disease.
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