Bacterial and Host Factors in Staphylococcus aureus Septic Arthritis

Abstract

The intense battle against Staphylococcus aureus (S. aureus) infections, along with the ongoing struggle to develop new effective treatments, presents a major challenge for the healthcare system. This highly pathogenic bacteria have a vast range of virulence factors, including phenol-soluble modulins (PSMs) at its disposal. Importantly, S. aureus is attributable to a broad spectrum of clinical infections in humans, not least bacteremia and the joint debilitating disease, septic arthritis. The aim of this thesis was to uncover bacterial virulence factors and host factors that are critical for the progression of septic arthritis induced by S. aureus. The thesis also reviews recent therapeutic innovations targeting this challenging disease. Three key papers are included in this thesis, each addressing different aspects of S. aureus-induced infections in mouse models. Paper I investigates the role of PSMs, specifically PSMα and PSMβ, in the development of septic arthritis. The findings demonstrate that PSMα exacerbates systemic infection by impairing neutrophil function, leading to increased bacterial burden and more severe disease outcomes. Conversely, PSMβ appears to have a protective role, mitigating inflammation and reducing joint damage. These results suggest that targeting PSMα might reduce infection severity, while enhancing PSMβ activity could offer therapeutic benefits in treating septic arthritis. Paper II explores the impact of aging and Toll-like receptor 2 (TLR2) deficiency on the outcomes of S. aureus bacteremia. The study reveals that older mice and those deficient in TLR2 are more susceptible to severe infection outcomes, including higher mortality rates and impaired bacterial clearance. This highlights the crucial role of TLR2 in mediating an effective immune response against S. aureus, especially in vulnerable populations like the elderly. Paper III focuses on the mechanism of bone destruction in septic arthritis, particularly the role of osteoclast-mediated bone degradation. The results suggest that combining traditional antibiotic treatment with anti-RANKL therapy, which inhibits osteoclast activity, offers a promising approach to mitigating bone destruction in septic arthritis. This combination therapy could significantly improve treatment outcomes by addressing both infection and the resulting bone damage. Together, these studies provide a comprehensive understanding of the pathogenic mechanisms of S. aureus in septic arthritis and identify potential therapeutic targets to improve treatment outcomes.