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，其中大多数是由金黄色葡萄球菌引起的。 在此P50骨骼感染的骨气免疫学的研究中心之前 （Cortobi），众所周知，选修手术后的这些罕见感染（约1％），我们无法控制 它们（〜40％的再感染率）是由于特定的宿主 - 病原体相互作用引起的。而合并症相关 还知道感染，自适应免疫和金黄色葡萄球菌在临床结果上的作用 被研究。因此，Cortobi的项目2使用自定义多重免疫测定，整个基因组对此进行了测试 297例确认的S. 金黄色的感染。结果正式建立了抗GMD抗体作为保护性和抗ISDB抗体 作为免疫蛋白质组的敏感决定因素，几乎所有人都有敏感的免疫 蛋白质组。因此，我们现在假设：1）抗GMD与抗ISDB抗体分泌B中存在缺陷 细胞，血浆和/或长寿命的浆细胞（LLPC），负责天然易感的 免疫蛋白质组。 2）金黄色葡萄球菌特异性因子有助于敏感的免疫蛋白质组起源。 3）多价纳米颗粒mRNA疫苗可以逆转易感免疫蛋白质组。三 在此Cortobi更新中提出了针对项目2的具体目标。在AIM 1中，我们将阐明机制 易感抗S的金黄色免疫组蛋白质组发生通过量化抗GMD与抗ISDB特异性B细胞 在实验小鼠和金黄色葡萄球菌患者中，血液中的血浆和骨髓中的LLPC在骨髓中 感染与未感染的健康对照。在AIM 2中，我们将完成297 S.金黄色金黄色菌株的WG AO-CPP注册表，并鉴定与最差临床结果相关的菌株中的独特基因。和 在AIM 3中，我们将证明多价mRNA纳米颗粒疫苗的功效以克服 敏感的免疫蛋白质组对金黄色葡萄球菌，并保护小鼠免受与植入物相关的骨髓炎的影响。在 除GMD外，我们还证明了抗AMD，HLA，芯片和scin抗体显着 与骨髓炎患者的感染控制有关。鉴于mRNA纳米颗粒的历史成功 疫苗在COVID-19大流行期间，我们将使用该技术开发五种候选疫苗 抗原。将对单价疫苗进行剂量反应研究以确定最小的mRNA 在血清中诱导抗体> 10ng/mL的浓度。然后单声道和多价的功效 使用我们 植入物 - 缔解骨髓炎的预防性和治疗性鼠模型。总体影响：我们将 确定负责易感免疫蛋白质组的机制，建立候选mRNA疫苗 具有克服它的潜力，并将金黄色葡萄球菌菌株变量添加到我们的多参数列图中 治疗反应预测，可用于个性化预防和治疗。