Abstract
Staphylococcus aureus (S. aureus) is a commensal bacterium commonly found in our microbial flora. However, when it enters the bloodstream, it can act as an opportunistic pathogen causing disease, ranging from mild skin infections to life-threatening conditions when left untreated. Therefore, understanding the mechanisms that allow it to evade the immune system and thrive will allow more effective treatments to be developed. This is of particular importance given the growing risk of antibiotic resistance, which is restricting our current treatments.S. aureus releases a range of virulence factors which target all aspects of the immune system. Of particular interest are those factors that modulate our innate immune system (complement system), ordinarily responsible for continuously probing the local environment for invading pathogens. The S. aureus binder of IgG (Sbi) has been identified as one such molecule that targets this element of the immune system, utilising various mechanisms to evade detection and subsequent clearance. This includes its ability to regulate the central complement component C3, by preventing its activation and subsequent opsonisation near the microbial surface. Intriguingly activation can also be upregulated away from the cell surface causing futile consumption of local complement reserves.
This thesis aimed to study previously unexplored elements of Sbi and the complement system, to enhance our understanding of its known immune evasion mechanisms as well as identify novel ones. Further analysis of domain III of Sbi previously shown to interact with C3, its breakdown fragments and associated regulators, facilitated the creation of an antibody fragment with tight binding and Sbi inhibitory properties. Dimeric versions of C3 fragments were observed and the structure and function of dimeric C3d was revealed. Additionally, their ability to interact with Sbi resulting in stabilisation was elucidated and implies a novel immune evasion mechanism Finally, experiments investigating the ternary complex associated with the futile consumption of C3, further confirmed this function although these findings were unable to elucidate the mechanism underlying this process. With additional research these findings could be used to develop novel complement-based therapeutics.
| Date of Award | 29 Mar 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jean Van Den Elsen (Supervisor) & Christiane Berger-Schaffitzel (Supervisor) |