Center of Research Translation on the Osteoimmunology of Bone Infection

摘要 假体关节感染(PJI)是择期全关节置换术(TJR)的祸害。 其中绝大多数是由葡萄球菌引起的。尽管初发感染人数 TJR低(1-5%)，再感染率很高(15%-40%)，这导致了骨科 金黄色葡萄球菌感染骨骼是不治之症的范例。此外，众所周知，PJI是非随机的 这在很大程度上是由患者特定因素决定的，因为感染只由少数人引起 流行的医院菌株(即MRSA USA300)，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%的感染S. 金黄色葡萄球菌会败血症并死于多器官衰竭，而其他金黄色葡萄球菌则在很少的干预下就能恢复。至 为了解决这些非常重要的问题，我们建议成立翻译研究中心 骨感染的骨免疫学(CoRTOBI)，这是两个非常成功的进化 计划(AO创伤骨感染临床优先计划(AO-CPP)和NIAMS P50 CORT AR54041《将分子信号通路转化为骨科创伤护理》)即将完成 今年。为了充分利用这些计划的显著优势，CoRTOBI现在建议 关于金黄色葡萄球菌感染骨骼和宿主的AO-CPP主要发现的进展和翻译 豁免，使用经过证明的P50 Cort的行政结构。这些发现包括：1)S. 活骨的骨细胞-管状网络的金黄色定植，2)新型抗生素， 专门针对这些机构，它们可以3D打印到定制间隔中，3)开发 一种用于阐明金黄色葡萄球菌免疫蛋白质组的定制多重Luminex方法，以及4)鉴定 抗ISD与抗AT1免疫蛋白质组比作为宿主免疫易感与保护指标的比较 对抗金黄色葡萄球菌。拟议的CoRTOBI将由一个行政核心组成，该核心将提供 CoRTOBI的业务和财务管理，以及临床研究分核心，a 生物统计学分核心，一个浓缩计划，以及一个试点和可行性项目计划。确实有 两个研究项目。项目1的重点是阐明金黄色葡萄球菌的运动机制。 骨和开发新型抗生素浸渍3D打印间隔物。项目2的重点是定义 葡萄球菌骨髓炎的易感和保护性免疫蛋白质组及干预措施 败血症死亡。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。在结束时 通过这项研究，我们将对骨感染的微生物发病机制有了新的认识 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.