Defining the Protective vs. Susceptible Immune Proteome of S. aureus Osteomyelitis

定义金黄色葡萄球菌骨髓炎的保护性与易感性免疫蛋白质组

• 批准号: 10402967
• 负责人: Edward M. Schwarz
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402967
• 关键词: Animal Model; Antibodies; Antigens; B-Lymphocytes; Biological Assay; Biological Markers; Blood; Bone Marrow; COVID-19 pandemic; Clinical; Custom; DNA sequencing; Defect; Dose; Emergency Department patient; Funding; Genes; Glucosaminidase; Goals; Immune; Immunoassay; Immunoglobulin-Secreting Cells; Immunologic Tests; Immunologics; Implant; Infection; Infection Control; Integration Host Factors; Iron; Messenger RNA; Methods; Modeling; Monoclonal Antibodies; Mus; Nomograms; Odds Ratio; Operative Surgical Procedures; Orthopedic Surgery; Osteomyelitis; Outcome; Paper; Patients; Persons; Plasma Cells; Plasmablast; Population; Prediction of Response to Therapy; Predisposition; Prophylactic treatment; Proteome; RNA vaccine; Registries; Research; Risk Factors; Role; Staphylococcus aureus; Staphylococcus aureus infection; Technology; Testing; Therapeutic; Time; Translational Research; Trauma; Vaccines; Virulence Factors; Virulent; Work; adaptive immunity; adverse outcome; comorbidity; experience; genome sequencing; infection rate; methicillin resistant Staphylococcus aureus; mouse model; nanoparticle; osteoimmunology; pathogen; prognostic; prophylactic; response; success; vaccine candidate; virtual; whole genome

Abstract Osteomyelitis is the bane of orthopaedic surgery, of which the majority is caused by Staphylococcus aureus. Prior to this P50 Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI), it was known that these rare infections following elective surgery (~1%), and our inability to control them (~40% reinfection rate), are due to specific host-pathogen interactions. While co-morbidities associated with infection were also known, the roles of adaptive immunity and S. aureus strain on clinical outcome had yet to be studied. Thus, Project 2 of CoRTOBI tested this using custom multiplex immunoassays, whole genome sequencing (WGS), animal models, and the AO-CPP Bone Infection Registry of 297 patients with confirmed S. aureus infection. The results formally established anti-Gmd antibodies as protective and anti-IsdB antibodies as susceptible determinants of the immune proteome, and that virtually all people have a susceptible immune proteome. Thus, we now hypothesize that: 1) there is a defect in anti-Gmd vs. anti-IsdB antibody secreting B cells, plasmablasts and/or long-lived plasma cells (LLPCs) that is responsible for the native susceptible immune proteome. 2) S. aureus strain specific factors contribute to susceptible immune proteome genesis. And, 3) multivalent nanoparticle mRNA vaccines can reverse the susceptible immune proteome. Three Specific Aims are proposed for Project 2 in this CoRTOBI renewal. In Aim 1 we will elucidate the mechanism of susceptible anti-S. aureus immune proteome genesis by quantifying anti-Gmd vs. anti-IsdB specific B cells and plasmablasts in blood, and LLPCs in bone marrow, in experimental mice and patients with S. aureus bone infections versus uninfected healthy controls. In Aim 2 we will complete WGS of the 297 S. aureus strains in the AO-CPP registry, and identify unique genes in the strains associated with the worst clinical outcomes. And in Aim 3 we will demonstrate the efficacy of multivalent mRNA nanoparticle vaccines to overcome the susceptible immune proteome against S. aureus, and protect mice from implant-associated osteomyelitis. In addition to Gmd, we have also demonstrated that anti-Amd, Hla, CHIPS & SCIN antibodies are significantly associated with infection control in osteomyelitis patients. Given the historic success of mRNA nanoparticle vaccines during the COVID-19 pandemic, we will use this technology to develop candidate vaccines for the five antigens. Dose response studies will be performed for monovalent vaccines to determine the minimal mRNA concentration that can induce antibodies >10ng/ml in sera. Then the efficacy of the mono and multivalent vaccines will be tested against the most virulent S. aureus strains in the AO-CPP registry using our prophylactic and therapeutic murine models of implant-associate osteomyelitis. Overall Impact: We will identify the mechanism responsible for the susceptible immune proteome, establish candidate mRNA vaccines with potential to overcome it, and add S. aureus strain variables into our multiparametric nomogram for pre-op treatment response prediction, which could be used for personalized prophylaxis and treatments.

抽象的 骨髓炎是骨科手术的祸根，其中大部分是由金黄色葡萄球菌引起的。 在此之前 P50 骨感染骨免疫学研究翻译中心 （CoRTOBI），众所周知，择期手术后这些罕见的感染（~1％），并且我们无法控制 它们（约 40% 的再感染率）是由于特定的宿主-病原体相互作用造成的。虽然合并症相关 感染后，适应性免疫和金黄色葡萄球菌菌株对临床结果的作用尚不清楚 有待研究。因此，CoRTOBI 的项目 2 使用定制多重免疫分析、全基因组测试了这一点 测序（WGS）、动物模型和 297 名确诊为金黄色葡萄球菌的患者的 AO-CPP 骨感染登记。 金黄色葡萄球菌感染。结果正式确立抗Gmd抗体和抗IsdB抗体作为保护性抗体 作为免疫蛋白质组的易感决定因素，并且几乎所有人都具有易感免疫 蛋白质组。因此，我们现在假设： 1) 分泌 B 的抗 Gmd 与抗 IsdB 抗体存在缺陷 细胞、浆母细胞和/或长寿命浆细胞 (LLPC) 负责天然易感性 免疫蛋白质组。 2) 金黄色葡萄球菌菌株特定因素有助于易感免疫蛋白质组的发生。 并且，3) 多价纳米颗粒 mRNA 疫苗可以逆转易感的免疫蛋白质组。三 本次 CoRTOBI 更新中为项目 2 提出了具体目标。在目标 1 中，我们将阐明其机制 易感抗-S。通过量化抗 Gmd 与抗 IsdB 特异性 B 细胞来确定金黄色葡萄球菌免疫蛋白质组起源 实验小鼠和金黄色葡萄球菌骨患者的血液中的浆母细胞和骨髓中的 LLPC 感染与未感染的健康对照。在目标 2 中，我们将完成 297 个金黄色葡萄球菌菌株的全基因组测序 (WGS) AO-CPP 注册表，并识别与最差临床结果相关的菌株中的独特基因。和 在目标 3 中，我们将展示多价 mRNA 纳米颗粒疫苗的功效，以克服 针对金黄色葡萄球菌的敏感免疫蛋白质组，并保护小鼠免受植入相关的骨髓炎。在 除了 Gmd 之外，我们还证明抗 Amd、Hla、CHIPS 和 SCIN 抗体显着 与骨髓炎患者的感染控制有关。鉴于 mRNA 纳米粒子的历史性成功 在COVID-19大流行期间，我们将利用这项技术来开发五种候选疫苗 抗原。将对单价疫苗进行剂量反应研究以确定最小 mRNA 可以在血清中诱导抗体 >10ng/ml 的浓度。那么单价和多价的功效 疫苗将使用我们的 AO-CPP 注册表中毒性最强的金黄色葡萄球菌菌株进行测试 植入相关骨髓炎的预防性和治疗性小鼠模型。总体影响：我们将 确定易感免疫蛋白质组的机制，建立候选 mRNA 疫苗 有潜力克服它，并将金黄色葡萄球菌应变变量添加到我们的多参数列线图中以进行术前 治疗反应预测，可用于个性化预防和治疗。