The impact of Staphylococcus aureus surface proteins on virulence

Sammanfattning: Staphylococcus aureus is an important pathogen in humans with the potential to cause life-threatening invasive infections, including sepsis and septic arthritis. The pathogenicity of S. aureus depends on the expression of a variety of virulence factors. The objective of this thesis was to investigate the role of certain cell wall-anchored proteins of S. aureus in the establishment and progression of murine septic arthritis. Specifically, the virulence contributions of the immunoglobulin-binding staphylococcal protein A (SpA), the fibrinogen-binding clumping factors (Clfs), and the fibronectin-binding proteins (Fnbps) were studied. Also, potential mechanisms by which these proteins could contribute to staphylococcal virulence and host interaction were investigated.Wild-type S. aureus strains and defined gene knock-out mutants, i.e. strains deficient with respect to expression of one or several cell wall-anchored proteins, were compared with respect to their abilities to induce arthritis and systemic inflammation following intravenous inoculation of mice. The role of the interaction between clumping factor A (ClfA) and fibrinogen for staphylococcal virulence was studied by defibrinogenation of mice with ancrod. Also, bacteriological, serological and histological analyses were performed ex vivo. In vitro assays for macrophage phagocytosis, spleen cell proliferation, and pro-inflammatory cytokine/chemokine release were also used.Expression of SpA and the Clfs contributed to the development of septic arthritis, and SpA to systemic inflammation. In contrast, expression of the Fnbps had no impact on arthritis development, but triggered severe systemic inflammation in infected mice, characterized by IL-6 production, weight loss and mortality.SpA expression by S. aureus was shown to trigger supraclonal B-cell responses in vivo and spleen cell proliferation in vitro. Expression of ClfA by S. aureus impeded macrophage phagocytosis in a fibrinogen-independent manner, and contributed to the immunostimulatory property of S. aureus. ClfA-mediated arthritogenicity was retained despite fibrinogen depletion of mice, indicating that ClfA contributes to staphylococcal virulence through as yet unidentified mechanisms.In summary, this thesis identifies SpA, Clfs, and Fnbps as virulence factors of S. aureus. SpA and Clfs are arthritogenic factors, whereas SpA and Fnbps contribute to the induction of systemic inflammation and mortality. These surface proteins should be evaluated as targets for vaccination against S. aureus infections.