Staphylococcus aureus abscess communities and osteomyelitis Host-pathogen interactions in vitro and in vivo

Staphylococcus aureus is the main causative pathogen of osteomyelitis and fracture-related infections (FRI). Once these infections become chronic, they are more difficult to treat. To identify new treatment targets for osteomyelitis and FRI, this thesis investigated mechanisms that S. aureus employs to survive within bone and bone marrow during these infections and why immune responses are unable to clear the infection. We found that S. aureus grows as staphylococcal abscess communities (SAC) within a fibrin pseudocapsule in bone marrow of FRI mice. Around the SAC were many neutrophils with some monocytes and M2 macrophages that were unable to penetrate the SAC, which created an abscess. With a developed 3D in vitro SAC model, we determined that the fibrin pseudocapsule and the tightly packed nature of a SAC act as physical barriers and protect S. aureus within a SAC from neutrophil and antibiotic exposure. Furthermore, experiments revealed that in vitro SACs cause human and murine bone marrow cells to adopt an immunosuppressive phenotype and to become myeloid-derived suppressor cells (MDSCs), and potential mediators of this were identified. MDSCs with M2 macrophages and regulatory T cells were present in SACs- and abscesses-containing bone marrow of FRI mice as well. Lastly, we could not substantiate that the S. aureus secreted pore-forming toxin Panton-Valentine leucocidin (PVL) influences the pathogenicity of S. aureus during an implant-associated osteomyelitis in mice. Overall, this thesis gave more insight into the pathophysiology of an S. aureus-induced osteomyelitis and FRI and revealed potential new targets for future investigations.