Date of Award

2012

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Steven W. Kerrigan

Keywords

Osteomyelitis, Staphylococcus Aureus, Staphylococcus Epidermidis

Abstract

Osteomyelitis is a debilitating infectious disease of the bone. It is mainly caused by Staphylococcus aureus and Staphylococcus epidermidis, being the second one, the major cause of implant-related osteomyelitis. Osteomyelitis is associated with significant morbidity and mortality and it is mainly characterised by weakened bones due to progressive bone loss and in flammation . However, currently the mechanism through which either bone destruction or inflammation occurs in osteomyelitis patients is poorly understood. The data presented in this thesis shows that S. aureus and S. epidermidis bind differently to bone and follow distinct pathways in the initiation and progression of disease. While S. epidermidis interacts with osteoblast via SdrG binding to fibrinogen which in turn binds to an integrin receptor on the osteoblast surface, S. aureus uses a very specific interaction mediated by S. aureus protein A (SpA) and Tum or Necrosis factor receptor 1 (TNFR-1) to bind osteoblast. A study of the interaction between S. epidermidis and osteoblast demonstrated that S.epidermidis SdrG protein is involved in the inhibition of osteoblast growth but not in osteoblast d e a th following infection. On the othe r hand, investigation of the effect following SpA binding to TNFR-1 revealed this to be crucial in the activation o f the receptor pathway mediating multiple signals ultimately leading to suppression of bone growth together with bone destruction and inflammation . Here, it is shown th at upon infection with S. aureus, osteoblasts undergo apoptosis, through caspase 3 cleavage, and the activation of inflammatory processes occurs via NFkB activation associated with IkB degradation and the release of IL6. All of these events were prevented when blocking SpA or TNFR-1 or both, confirming the importance of this interaction in the onset and development of disease. The findings presented in this thesis describe for the first time interactions between Staphylococci and osteoblast and th e ir role in the progression of Staphylococcal induced osteomyelitis. Furthermore, this study may also highly contribute for the development of a novel or improved therapy for osteomyelitis patients using th e TNFR-1.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

4,456 KB

Comments

A thesis submitted to the National University of Ireland for the degree of Doctor of Philosophy

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