Evaluating the Functional Antibody Response to Pediatric S. aureus Infections

评估儿童金黄色葡萄球菌感染的功能性抗体反应

• 批准号: 9310138
• 负责人: Isaac P Thomsen
• 金额: $ 18.55万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310138
• 关键词: Academic Medical Centers; Address; Age; Anterior nares; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Antimicrobial Resistance; Award; Binding; Biological Assay; Characteristics; Child; Childhood; Clinical; Clinical Data; Cohort Studies; Communicable Diseases; Cytolysis; Development; Dimerization; Disease; Educational workshop; Emergency Situation; Enrollment; Environment; Exhibits; Exotoxins; Funding; Future; Goals; Government; Hospitals; Human; Immune Evasion; Immune response; Immunity; Immunologic Techniques; Immunologist; Immunology; In Vitro; Infection; Infectious Skin Diseases; Innate Immune Response; Institute of Medicine (U.S.); Integration Host Factors; International; Investigation; K-Series Research Career Programs; Kinetics; Laboratories; Laboratory Study; Longitudinal Studies; Lytic; Master of Science; Mediating; Medical; Mentors; Mentorship; Methods; Molecular Conformation; Molecular Epidemiology; Monoclonal Antibodies; New York; Organism; Pathogenesis; Patients; Pediatrics; Phenotype; Physicians; Pilot Projects; Play; Population; Positioning Attribute; Prevention; Prevention strategy; Preventive; Prospective cohort; Publishing; Recurrence; Reporting; Research; Research Personnel; Research Proposals; Research Training; Risk; Role; Scientist; Serum; Skin; Societies; Soft Tissue Infections; Staphylococcus aureus; Study Subject; Symbiosis; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxin; Training; Training Programs; Translational Research; United States; Universities; Vaccines; Virulence Factors; Work; adaptive immune response; career; clinical investigation; clinical phenotype; cohort; college; cytotoxic; cytotoxicity; dimer; disorder prevention; experience; human monoclonal antibodies; improved; insight; interest; leukotoxin; medical schools; methicillin resistant Staphylococcus aureus; neutralizing antibody; neutrophil; novel; novel therapeutics; pathogen; patient oriented research; polyclonal human antibody; prevent; professor; prospective; public health relevance; response; translational scientist; vaccinology

DESCRIPTION (provided by applicant): The overarching goal of this career development award is to provide a comprehensive training program to prepare the candidate for an independently funded translational research career focused on the host- pathogen interactions of the major bacterial pathogen, Staphylococcus aureus. The candidate, Dr. Isaac Thomsen, is an Assistant Professor of Pediatrics in the Division of Pediatric Infectious Diseases at Vanderbilt with an advanced degree in patient-oriented research (Masters of Science in Clinical Investigation, MSCI). The proposed research directly examines key gaps in the current understanding of the human immune response to S. aureus. The candidate's near-term goal is to acquire additional expertise in adaptive immunology and molecular epidemiology while continuing a productive line of investigation into the role of the humoral immune response to staphylococcal colonization and disease in children. This award will allow the candidate to fulfill this goal with formal, graduate-level coursework, workshops in key immunological techniques, and protection for 5 years of mentored research. The proposed studies will be conducted over the next several years as part of a comprehensive training experience under the direction of the candidate's co-mentors Drs. Kathryn Edwards and Buddy Creech. Dr. Creech is an established investigator in the field of S. aureus research and was the recipient of the IDSA/SHEA Young Investigator Award in MRSA Research in 2007 and the 2012 PIDS Young Investigator Award. He has published extensively in the field of staphylococcal colonization, molecular epidemiology, antimicrobial resistance, and therapeutics. He will serve as the "hands-on", translational science mentor for this project. Dr. Edwards is an internationally recognized expert in pediatric infectious diseases and vaccinology. While maintaining a highly productive research portfolio, Dr. Edwards has also dedicated herself to nurturing the careers of young investigators, and has developed a strong track record for mentoring investigators who go on to obtain independent government funding. Dr. Edwards has received numerous accolades, including the 2006 IDSA Mentor of the Year Award, election to the Institute of Medicine in 2008, and selection as the Outstanding Physician of the Year by the Pediatric Infectious Disease Society in 2011. In addition, Vanderbilt University Medical Center provides a rich environment for research and training of young investigators with centralized oversight of all mentored physician scientists through the Office of Clinical & Translational Scientist Development. Dr. Thomsen's long-term goal is to become an independently funded physician-scientist bridging both human and laboratory studies in staphylococcal immunity research, ultimately identifying novel targets for prevention and treatment of S. aureus. The strong mentorship, additional training, and environment detailed in this proposal will position him to ultimately reach this objective. The research proposal extends the candidate's prior published work on the host and pathogen interactions in pediatric staphylococcal colonization and disease. S. aureus harmlessly colonizes the anterior nares of nearly 1/3 of the population, yet leads to severe, invasive disease in some. The factors that govern this relationship are poorly understood, and this remains a barrier to the development of preventive and therapeutic agents. The candidate's recent work in children with invasive staphylococcal disease led to novel findings regarding the neutralizing antibody response to an important, recently-described toxin known as LukAB. The proposed work is focused on the hypothesis that a high-level, functional antibody response against this toxin is protective against the development of invasive or recurrent S. aureus disease. In Aim 1, the candidate will develop prospective cohorts of children with each of the four major phenotypes of S. aureus infection (colonization, skin infections, recurrent skin infections, and invasive disease), and will examine the anti-staphylococcal antibody profile in these cohorts over time, leading to correlations between specific antibody titers and clinical disease characteristics. In Aim 2, well-established functional antibody assays will allow the determination of antibody function (in the prevention of neutrophil lysis by staphylococcal exotoxins) and the correlation of this neutralizing activity with clinical phenotypes. In Aim 3, th candidate will extend his work on the development of human-derived monoclonal antibodies against LukAB. By determining the binding and neutralizing capacity of anti-LukAB antibodies against each subunit of the toxin, new insights will be gained into the mechanism of the cytoprotective effects of naturally occurring anti-LukAB antibodies following S. aureus disease in humans. Key collaborators in this work include Dr. James Crowe, a world-renowned immunologist at Vanderbilt and an expert in human monoclonal antibodies, and Dr. Victor Torres at the New York University School of Medicine, a well-recognized expert in staphylococcal pathogenesis and S. aureus exotoxins. This project will advance an understanding of the antibody response to S. aureus colonization and disease and will examine the potential of specific staphylococcal virulence factors as targets for future vaccines or novel therapeutic agents.

描述（由申请人提供）：该职业发展奖的总体目标是提供一项全面的培训计划，为候选人做好准备的独立资助的转化研究职业，重点是主要细菌病原体葡萄球菌金黄色葡萄球菌的宿主病原体相互作用。候选人艾萨克·汤姆森（Isaac Thomsen）博士是范德比尔特（Vanderbilt）小儿传染病科儿科助理教授 具有以患者为导向的研究（临床研究硕士学位，MSCI）。拟议的研究直接研究了当前对人类免疫反应对金黄色葡萄球菌的免疫反应的关键差距。 候选人的近期目标是获得适应性免疫学和分子流行病学方面的额外专业知识，同时继续研究对儿童葡萄球菌定殖和疾病的体液免疫反应的作用。该奖项将使候选人能够履行 这一目标是通过正式的研究生课程，关键免疫技术的讲习班以及5年的指导研究的保护。拟议的研究将在接下来的几年中作为在候选人的联合委员会DR的指导下进行全面培训经验的一部分进行。凯瑟琳·爱德华兹（Kathryn Edwards）和好友克里奇（Buddy Creech）。 Creech博士是S. Aureus Research领域的既定研究者，并获得了2007年MRSA研究的IDSA/SHEA YOUNG研究者奖和2012年PIDS Young Nought Noverseator Award。他已广泛发表在葡萄球菌定殖，分子流行病学，抗菌耐药性和治疗学领域。他将担任该项目的“动手”，转化科学的导师。爱德华兹博士是一位国际公认的小儿传染病和疫苗学专家。爱德华兹（Edwards）博士在维护高产研究组合的同时，还致力于培养年轻调查员的职业，并为继续获得独立政府资金的指导调查员建立了良好的记录。爱德华兹博士（Edwards博士）获得了许多赞誉，包括2006年年度IDSA年度指导者奖，2008年选举给医学研究所，并于2011年被儿科感染疾病社会作为年度杰出医师。此外，范德比尔特大学医学中心还为所有培养业人士的集中式医学培训的年轻调查员提供了一项丰富的研究和培训，该研究人员还通过培养了临时及其培训的集中式培训。 汤姆森博士的长期目标是成为葡萄球菌免疫研究中人类和实验室研究的独立资助的医师科学家，最终确定了用于预防和治疗金黄色葡萄球菌的新目标。该提案中详细介绍的强大指导，额外的培训和环境将使他最终达到这一目标。该研究提案扩展了候选人在小儿葡萄球菌定殖和疾病中关于宿主和病原体相互作用的先前发表的工作。金黄色葡萄球菌无害地殖民了近1/3人口的前鼻孔，但在某些人群中导致严重的侵入性疾病。控制这种关系的因素知之甚少，这仍然是预防和治疗剂发展的障碍。候选人最近在侵入性葡萄球菌疾病的儿童中的工作导致了有关对重要的，最近描述的毒素的中和抗体反应的新发现，称为卢卡布。拟议的工作集中在以下假设上：对这种毒素的高级功能抗体反应可抵抗侵入性或复发性金黄色葡萄球菌疾病的发展。 在AIM 1中，候选人将开发出与金黄色葡萄球菌感染的四种主要表型（定殖，皮肤感染，复发性皮肤感染和侵入性疾病）中的每种儿童的前瞻性人群，并将检查这些同伴的抗稳态抗体特征，这些抗体随时间及时，导致特定抗体疾病和临床疾病的特征。在AIM 2中，建立的功能抗体测定将允许确定抗体功能（在预防葡萄球菌外毒素中性粒细胞裂解中），并与这种中和活性与临床表型相关。在AIM 3中，第3名候选人将扩大他在针对卢卡布的人类衍生的单克隆抗体开发方面的工作。通过确定抗Lukab抗体与毒素每个亚基的结合和中和能力，将获得新的见解，从而获得人类天然抗lukab抗体自然存在的抗卢克巴抗体的细胞保护作用的机制。这项工作的主要合作者包括范德比尔特（Vanderbilt）世界著名的免疫学家詹姆斯·克劳（James Crowe）博士，人类单克隆抗体的专家，纽约大学医学院的维克多·托雷斯（Victor Torres）博士是葡萄球菌发病机理和绿色葡萄球菌蛋白质蛋白的良好认可的专家。该项目将进一步了解对金黄色葡萄球菌定植和疾病的抗体反应，并将研究特定的葡萄球菌毒力因子作为未来疫苗或新型治疗剂的靶标的潜力。