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

摘要 金黄色葡萄球菌引起的骨感染仍然是骨科手术的祸根，因为诊断， 预防和治疗有重大缺陷，会给患者带来灾难性的后果， 以及严重的医疗成本。尽管初次全关节置换术后感染的发生率 (TJR)很低(~1%)，再感染率很高(15%-40%)，这导致了S。 金黄色葡萄球菌感染是不治之症。此外，假体关节感染(PJI)被认为是一种非随机的 事件在很大程度上由患者特定的因素决定。为了解决这个问题，我们提出了最初的中心 骨感染的骨免疫学研究翻译(CoRTOBI)以验证假说 那就是：1)必须有一个不受标准护理治疗影响的金黄色葡萄球菌宿主，以及2) 患者对金黄色葡萄球菌抗原的免疫蛋白质组影响骨感染的发生率和预后。 我们在这方面的工作已经产生了创新的技术，这些技术正在被行业转化为临床 合作伙伴，以及我们将在这次更新中继续努力的几个开创性发现，包括：1)S。 活骨骨细胞陷窝管网(OLCN)的金黄色定植，2)新型小分子 专门针对这些机制的抑制剂，可以3D打印到定制间隔物中作为佐剂 抗生素，3)建立了一种定制的多重免疫分析方法，以阐明链球菌的免疫蛋白质组。 金色，4)开发活体成像以实时量化植入物的“表面竞赛”，以及5) 抗ISDB应答为易感免疫，抗GMD应答为保护性免疫 小鼠和患者培养证实金黄色葡萄球菌骨感染。基于这一成功，我们建议 继续执行CoRTOBI及其行政核心，提供业务和财政管理 CoRTOBI，以及一个生物统计分核心、一个浓缩方案以及一个试点和可行性项目 程序。我们还将继续开展研究项目。项目1的重点是阐明 美国金黄色葡萄球菌入侵OLCN，并开发新型抗生素和佐剂浸渍3D打印 间隔器。项目2的重点是阐明易感免疫蛋白质组的机制。 在患者身上，将我们发现的五种保护性抗原转化为一种新的多价mRNA疫苗，以及 患者感染金黄色葡萄球菌菌株的特定因素的生物信息学评估。 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、微制造和免疫分析。核心还将进一步创新这些技术 转化为新的结果衡量标准，并增强其对商业产品的临床实用性。在结束时 对于这种CoRTOBI，我们将对金黄色葡萄球菌的OLCN入侵和免疫逃避以及 用于诊断、预防和治疗最严重疾病的新的候选临床检测方法、抗菌剂和疫苗 骨感染，其结果在过去半个世纪中没有改善。

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.