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Title: Molecular analysis of the human antibody response to antigens of Staphylococcus aureus
Author: Wright, Andrew
ISNI:       0000 0001 3572 9991
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2006
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Staphylococcus aureus is a significant cause of Gram-positive sepsis and infection in the nosocomial environment, and has given rise to the MRSA 'superbug'. The identification of multi-drug resistant strains of S. aureus has advanced the search for new targets for S. aureus prophylaxis or therapy. Such strategies may include the identification of novel S. aureus vaccine candidates, or the production of antibodies to appropriate S. aureus antigens for passive immunization. Previous studies have identified antibodies specific to the major cell wall antigen peptidoglycan as important in the opsonisation of S. aureus, facilitating uptake into phagocytic cells and removal from the host. In agreement with others, our studies have shown antibodies to peptidoglycan and its derivatives are present throughout the population over a wide concentration range and are found in sera from both 'normal' control donors and S. aureus infected individuals. In an attempt to dissect the antibody response to peptidoglycan at the molecular level we have created recombinant human single-chain antibody libraries from the genetic material of such donors, and have screened them for the presence of peptidoglycan specific antibodies. Despite extensive analysis and optimisation of'the library construction and screening process, we were unable to isolate such antibodies from our libraries. However, analysis of a large 'singlepot' synthetic library of antibody variable region genes did lead to the retrieval of two antibodies specific for cellosyl-digested S. aureus peptidoglycan. These antibodies were characterised with respect to antigen binding sensitivity and specificity. This study has also focused on the immune response to CHIPS (the chemotaxis inhibitory protein of Staphylococcus aureus), a recently identified virulence determinant of S. aureus capable ofinhibiting the recruitment ofleukocytes to the site ofbacterial invasion. We have demonstrated the presence of antibodies to CHIPS throughout the population of sera examined. Using a model cell system, we have also identified a role for a high level of anti-CHIPS antibodies in either the inhibition or enhancement of bacterial pathogenesis by modulating binding of CHIPS to the C5a receptor, CD88.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available