Bone infection, primarily caused by Staphylococcus aureus, remains the bane of orthopaedic surgery. Although the incidence of infection following primary total joint replacement (TJR) is low (~1%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, prosthetic joint infection (PJI) is known to be a non-random event that is largely determined by patient-specific factors. To address this, we proposed the original Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI) to test the hypotheses that: 1) there are reservoirs of S. aureus that are not affected by standard of care treatments, and 2) the patient’s immune proteome against S. aureus antigens impacts the incidence and outcome of bone infection. Our work on this has resulted in 33 publications, 6 patented technologies that are being translated to the clinic by industry partners, and several seminal discoveries that remain the focus of this renewal. These, include: 1) S. aureus colonization of the osteocyte lacuno-canalicular network (OLCN) of live bone, 2) novel antibiotic adjuvants that specifically target these mechanisms that can be 3D-printed into custom spacers, 3) custom multiplex immunoassays to elucidate the immune proteome of S. aureus, 4) in vivo imaging to quantify “the race for the surface” of implants in real time, and 5) identification of anti-IsdB responses as susceptible immunity vs. anti- Gmd responses as protective immunity in mice and patients with culture confirmed S. aureus bone infection. In this renewal, the Administrative Core will provide operational and fiscal management of the CoRTOBI. It will also support clinical research and biostatistical needs, facilitate communications, run the Enrichment Programs, and maintain the Pilot and Feasibility Project Program (PFPP). The Specific Aims of the Administrative Core are to: Aim 1. Govern the entire CoRTOBI, which includes administration of personnel, financial oversight, and quality controls on services and research progress through evaluations at scheduled meetings. Aim 2. Foster communications between CoRTOBI Project & Core investigators, the IAC & EAC, our NIH-funded CTSAs, NIH/NIAMS Program staff, and the greater scientific community. Aim 3. Coordinate cost- effective access to the Research Cores. Aim 4. Maintain our successful Pilot and Feasibility Project Program (PFPP) in Bone Infection. Aim 5. Patent new intellectual property and collaborate with industry partners. And, Aim 6. Provide enrichment opportunities for CoRTOBI investigators, bone infection researchers, orthopaedic surgeons, and the larger scientific and lay communities. At the conclusion of this renewed P50 CoRTOBI, we will have: 1) elucidated novel mechanisms of S. aureus colonization of bone, 2) identified novel antibiotic adjuvants, and demonstrate their use in 3D-printing spacers for 1-stage revision, 3) defined the mechanism of susceptible immune proteome genesis, and develop mRNA nanoparticle vaccines to overcome it, and 4) generated a comprehensive algorithm to predict infection and clinical outcomes.