Structural and functional analysis of Staphylococcus aureus immune evasion proteins

Abstract

Staphylococcus aureus is a common commensal organism and a clinically important pathogen. S. aureus is able to establish infection in a range of tissues owing to its production of a wide variety of proteins which aid its invasion, attachment and immune evasion. Characterisation of S. aureus proteins is required to deepen understanding of infection and immunity and for continued development of antibacterial therapy. Extracellular fibrinogen binding protein, Efb, binds both fibrinogen and complement components. The C-terminal complement modulating domain of Efb, Efb-C, is well characterised. NMR data analysis suggests that the N-terminal fibrinogen binding region of Efb is natively unstructured. Previously characterised fibrinogen binding domains of S. aureus proteins are typically structured and so Efb may show a novel mechanism of fibrinogen binding. Staphylococcal binder of immunoglobulin, Sbi, confers host immune evasion through binding to both immunoglobulins and complement components. The solution structure of the complement binding domain of Sbi, Sbi IV, has been determined and reveals a conformation seen in other complement modulating proteins of S. aureus. The effect of Sbi IV and Efb on the complement activation pathways has been investigated and reveals key differences in the action of each of these proteins. The crystal structure of Sbi IV in complex with C3d has been determined and reveals that the interaction of Sbi IV with C3d is similar to that of other complement modulating proteins with C3d. NMR and X-ray diffraction data also reveal a potential second physiologically relevant mode of Sbi IV – C3d binding. Immunodominant staphylococcal antigen B, IsaB, is an uncharacterised protein whose expression may be correlated with immune evasion. NMR data indicate that IsaB adopts a folded conformation in solution but results of preliminary functional analyses of IsaB are currently unclear.

Date of Award	1 Sept 2009
Original language	English
Awarding Institution	University of Bath
Supervisor	Jean Van Den Elsen (Supervisor) & Stefan Bagby (Supervisor)