|Simpson, Charlotte Louise
|Simpson, C.L. 2015. Molecular Mechanisms Regulating the Epithelial Barrier: Key Roles for Cx26 and ADAM17 during Bacterial Infection. Queen Mary University of London.
|This study investigated how gastrointestinal and skin bacterial infections were
affected by differential expression of connexin (Cx) 26 and a disintegrin and
metalloprotease (ADAM) 17 in vitro.
Cx26 is a component of gap junctions, which facilitate the transfer of small
molecules between two cells. Recessive mutations in Cx26 cause non
syndromic hearing loss (NSHL), and in certain populations, specific mutations
account for the majority of Cx26 related NSHL. Their common occurrence
suggests that they may provide a heterozygous, protective advantage to
carriers. In this study adherence by the attaching and effacing pathogen
Enteropathogenic Escherichia coli (EPEC) was significantly reduced in cells
expressing mutant Cx26 compared to wild type Cx26. Furthermore, EPEC
adherence and invasion of an alternative enteric pathogen, Shigella flexneri
were reduced following treatment with Cx26 short-interfering-RNA in intestinal
cells. These findings suggest that the loss of functional Cx26 expression
improves protection against enteric bacteria.
ADAM17 releases substrates including tumour necrosis factor alpha and
ligands of the epidermal growth factor receptor and therefore is involved in the
induction of immune responses and maintenance of the epidermal barrier. This
study demonstrated that ADAM17 provides protection during Staphylococcus
aureus infection of keratinocytes. Subsequently the protective effects of
ADAM17 mediated protection were explored. Secretion of the proinflammatory
cytokines Interleukins 6 and 8 correlated with ADAM17 activity. Additionally
gene expression profiling was performed which identified the IL-17 signalling
pathway, which is known to be important during S. aureus infection, as a
potential downstream target of ADAM17.
In summary, based on these findings, Cx26 and ADAM17 may represent
potential therapeutic targets for gastrointestinal and skin bacterial pathogens
|Barts and the London School
of Medicine and Dentistry; Medical Research Council, UK
|Queen Mary University of London
|Society for Psychical Research
|Molecular Mechanisms Regulating the Epithelial Barrier: Key Roles for Cx26 and ADAM17 during Bacterial Infection.
|The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author