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Title: The role of tetraspanins in bacterial adhesion to human cells and the therapeutic potential of their peptide fragments
Author: Cozens, Daniel
ISNI:       0000 0004 5919 1438
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2015
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Tetraspanins are a superfamily of eukaryotic membrane-bound proteins involved in a wide array of cellular processes, such as adhesion and migration. They do this by forming large extended networks on the surface of the cell, known as tetraspanin-enriched microdomains (TEMs), whereby they can act as membrane organisers to partner proteins, including integrins and components of the immune system. This ensures these proteins are in conformations that aid in their function. Many of these partner proteins are also the receptors to which bacteria can adhere, using adhesins. TEMs may cluster these receptors together to allow for multiple interactions between pathogen and host, resulting in firm adhesion. It was shown that by disrupting the TEMs through pre-treatment of epithelial cells with a variety of recombinant tetraspanin extracellular domains (EC2s), it can significantly inhibit the ability of a bacterium to attach to a human epithelial cell line. Chimeric EC2 proteins highlighted important regions of the domain for achieving this phenomenon. This effect was successfully replicated using synthetic peptides based on regions of the CD9 EC2 peptide sequence, in a dose response-like fashion. This has been demonstrated using the bacterial pathogens Neisseria meningitidis, Streptococcus pneumoniae and Staphylococcus aureus. The antimicrobial protection is slowly lost from the cell over time, possibly due to recycling of the tetraspanins from the cell surface. The effect is likely due to disruption of the TEMs, as cholesterol depletion, which similarly disorders TEMs, removes the effect of subsequent treatment with synthetic peptides. EC2s of some tetraspanin molecules (particularly CD9 and CD63) and synthetic peptide derivatives show signs of promise for possible use as anti-adhesion therapeutics for treating bacterial infections. This could possibly be used in conjunction with current antibiotics, providing further protection to the patient during periods of sub-MIC levels of drugs between dosing.
Supervisor: Monk, Peter N. ; Read, Robert C. ; Partridge, Lynda J. ; MacNeil, Sheila Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available