Center of Research Translation on the Osteoimmunology of Bone Infection

摘要 人工关节感染（PJI）是择期全关节置换术（TJR）的祸根， 其中绝大多数是由葡萄球菌引起的。虽然原发性感染的数量 TJR后的感染率低（1-5%），再感染率非常高（1 - 5 -40%），这导致了骨科 范式S.金黄色葡萄球菌感染是无法治愈的。此外，PJI已知是非随机的 这在很大程度上取决于患者特定因素，因为感染仅由少数 流行的医院菌株（即MRSA USA 300），并实施最严格的外科手术 系统无法将感染率降低到1%以下。此外，约13%的患者感染了S. 金黄色葡萄球菌感染并死于多器官衰竭，而其他人几乎不需要干预就能康复。到 为了解决这些非常重要的问题，我们建议在 骨感染骨免疫学（CoRTOBI），是两种非常成功的骨免疫学的演变 计划（AOTrauma骨感染临床优先计划（AO-CPP）和NIAMS P50 CORT AR 54041“将分子信号通路转化为骨科创伤护理”）， 今年为了利用这些计划的突出优势，CoRTOBI现在建议 推进和转化AO-CPP在S.骨和宿主金黄色葡萄球菌感染 免疫力，使用P50 CORT的经验证的管理结构。这些发现包括：1）S. 活骨骨细胞-小管网络的金黄色葡萄球菌定植，2）新型抗生素， 专门针对这些机制，这些机制可以3D打印到定制的间隔物中，3）开发 定制的多重Luminex分析，以阐明S.金黄色葡萄球菌，和4）鉴定 抗-Isd与抗-Atl免疫蛋白质组比率作为宿主免疫的易感性与保护性指标 对于S.金黄色。拟议的CORTOBI将包括一个行政核心， CoRTOBI的运营和财务管理，以及临床研究子核心， 生物统计学子核心，一个浓缩方案，以及一个试点和可行性项目方案。有 两个研究项目。项目一是阐明S.金黄色葡萄球菌 骨和开发新型抗生素浸渍3D打印间隔器。项目2的重点是定义 葡萄球菌骨髓炎易感与保护性免疫蛋白质组及干预措施 脓毒性死亡这些项目将得到骨免疫学研究核心的支持，该核心将 提供最先进的成像、生物材料制造和免疫分析。结束时 通过这种CoRTOBI，我们将对骨感染的微生物发病机制和骨感染的微生物学机制有新的认识。 主机响应。我们还将为骨髓炎患者开发新的诊断和干预措施。

Abstract Prosthetic joint infection (PJI) is the bane of elective total joint replacement (TJR) surgery, of which the vast majority is caused by Staphylococcal species. Although the number of primary infections following TJR is low (1-5%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, PJI is known to be a non-random event that is largely determine by patient-specific factors, as infections are caused by only a few prevalent nosocomial strains (i.e. MRSA USA300), and implementation of the most rigorous surgical systems is incapable of reducing infection rates below 1%. Moreover, ~13% of patients infected with S. aureus become septic and die from multiorgan failure, while others recover with little intervention. To address these very significant issues, we propose the Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI), which is the evolution of two highly successful programs (AOTrauma Clinical Priority Program on Bone Infection (AO-CPP); and NIAMS P50 CORT AR54041 “Translating Molecular Signal Pathways to Orthopaedic Trauma Care”) that will be completed this year. To capitalize on the salient strengths of these programs, the CoRTOBI now proposes to advance and translate the major discoveries from the AO-CPP on S. aureus infection of bone and host immunity, using the proven administrative structure of the P50 CORT. These discoveries include: 1) S. aureus colonization of the osteocytic-canalicular network of live bone, 2) novel antibiotics that specifically target these mechanisms, which can be 3D-printed into custom spacers, 3) development of a custom multiplex Luminex assay to elucidate the immune proteome of S. aureus, and 4) identification of the anti-Isd vs. anti-Atl immune proteome ratio as a susceptible vs. protective index of host immunity against S. aureus. The proposed CoRTOBI will consist of an Administrative Core that will provide operational and fiscal management of the CoRTOBI, as well as a Clinical Research Sub-Core, a Biostatistics Sub-Core, an Enrichment Programs, and a Pilot and Feasibility Project Program. There are two Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus motility in bone and developing novel antibiotic impregnated 3D-printed spacers. Project 2 is focused on defining the susceptible vs. protective immune proteomes of Staphylococcus osteomyelitis and interventions for septic death. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, biomaterial fabrication and immunoassay analyses. At the conclusion of this CoRTOBI we will have new knowledge on the microbial pathogenesis of bone infection and the host response. We will also develop novel diagnostics and interventions for patients with osteomyelitis.