Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI)

摘要 由金黄色葡萄球菌引起的骨感染仍然是骨科手术的祸根，作为诊断， 药理学和治疗具有显著的缺点，导致患者的灾难性结果， 以及高昂的医疗费用。尽管初次全关节置换术后感染的发生率 (TJR)低（~1%），再感染率非常高（15-40%），这导致了S。 金黄色葡萄球菌感染是无法治愈的。此外，人工关节感染（PJI）是已知的非随机 这在很大程度上取决于患者的具体因素。为了解决这一问题，我们提出了最初的中心， 骨感染的骨免疫学研究翻译（CoRTOBI）以检验假设 （1）必须有一个S库。金黄色葡萄球菌，不受标准护理治疗的影响，和2） 患者的免疫蛋白质组对S.金黄色葡萄球菌抗原影响骨感染的发生率和结果。 我们在这方面的工作已经产生了创新的技术，这些技术正在被工业界转化为临床技术。 合作伙伴，和几个开创性的发现，我们将继续在这方面的工作，包括：1）S。 金黄色葡萄球菌定植的骨细胞腔隙-小管网络（OLCN）的活骨，2）新的小分子 特异性靶向这些机制的抑制剂，可以3D打印到定制的间隔物中作为佐剂， 抗生素，3）开发一种定制的多重免疫分析，以阐明免疫蛋白质组的S。 金黄色葡萄球菌，4）开发体内成像以真实的时间量化植入物的“表面竞争”，和5） 将抗-IsdB应答鉴定为易感性免疫，将抗-Gmd应答鉴定为保护性免疫， 小鼠和患者培养证实S.金黄色葡萄球菌骨感染。基于这一成功，我们建议 继续维持CoRTOBI及其行政核心，提供业务和财政管理， CoRTOBI，以及生物统计学子核心，丰富计划，以及试点和可行性项目 程序.我们还将继续开展研究项目。项目1的重点是阐明 S.金黄色葡萄球菌侵袭OLCN，并开发新型抗生素和佐剂浸渍3D打印 间隔物。项目2的重点是阐明易感免疫蛋白质组的机制 在患者中，将我们发现的五种保护性抗原转化为一种新型多价mRNA疫苗， 用S.他们感染的金黄色葡萄球菌。 该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、微加工和免疫分析。酷睿还将进一步创新这些技术 转化为新的结果测量，并增强其对商业产品的临床实用性。结束时 我们将深入了解S。金黄色葡萄球菌OLCN侵袭和免疫逃避，以及 新的候选临床检测、抗菌剂和疫苗，以诊断、预防和治疗最严重的 骨感染，其结果在过去的半个世纪没有改善。

Abstract Bone infection caused by Staphylococcus aureus remains the bane of orthopaedic surgery, as diagnostics, prophylactics and treatments have significant shortcomings that result in catastrophic outcomes for patients, and crippling healthcare costs. 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 must be a reservoir of S. aureus that is 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 innovative technologies that are being translated to the clinic by industry partners, and several seminal discoveries that we will continue to work on in this renewal, including: 1) S. aureus colonization of the osteocyte lacuno-canalicular network (OLCN) of live bone, 2) novel small molecule inhibitors that specifically target these mechanisms that can be 3D-printed into custom spacers as adjuvants to antibiotics, 3) development of a custom multiplex immunoassays to elucidate the immune proteome of S. aureus, 4) development of 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. Based on this success, we propose continuation of CoRTOBI with its Administrative Core that provides operational and fiscal management of the CoRTOBI, as well as a Biostatistics Sub-Core, an Enrichment Program, and a Pilot and Feasibility Project Program. We will also continue the Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus invasion of the OLCN, and developing novel antibiotic and adjuvant impregnated 3D-printed spacers. Project 2 is focused on elucidating the mechanism responsible for the susceptible immune proteome in patients, translating our discovery of five protective antigens with a novel multivalent mRNA vaccine, and bioinformatic assessment of patient-specific factors with the strain of S. aureus with which they are infected. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, microfabrication and immunoassay analyses. The Core will also further innovate these technologies into novel outcome measures and enhance their clinical utility towards commercial products. At the conclusion of this CoRTOBI we will have in-depth knowledge of S. aureus OLCN invasion and immune evasion, as well as novel candidate clinical assays, antimicrobials and vaccines, to diagnose, prevent and treat the most serious bone infections, whose outcomes have not improved over the last half century.