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全面的培训计划，为候选人准备独立资助的转化研究职业，重点关注主要细菌病原体金黄色葡萄球菌的宿主-病原体相互作用。该候选人艾萨克·汤姆森 (Isaac Thomsen) 博士是范德比尔特大学儿科传染病科的儿科助理教授 拥有以患者为导向的研究高级学位（临床研究理学硕士，MSCI）。拟议的研究直接检查了当前对人类对金黄色葡萄球菌免疫反应的理解中的关键差距。 该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更多专业知识，同时继续对体液免疫反应对儿童葡萄球菌定植和疾病的作用进行富有成效的研究。该奖项将使候选人能够满足 通过正式的研究生水平课程、关键免疫学技术研讨会以及 5 年指导研究的保护来实现这一目标。拟议的研究将在未来几年内进行，作为候选人共同导师 Drs. 的指导下综合培训经验的一部分。凯瑟琳·爱德华兹和巴迪·克里奇。 Creech 博士是金黄色葡萄球菌研究领域的资深研究员，曾荣获 2007 年 MRSA 研究领域的 IDSA/SHEA 青年研究员奖和 2012 年 PIDS 青年研究员奖。他在葡萄球菌定植、分子流行病学、抗菌素耐药性和治疗学领域发表了大量文章。他将担任该项目的“实践型”转化科学导师。爱德华兹博士是国际公认的儿科传染病和疫苗学专家。在保持高产的研究成果的同时，爱德华兹博士还致力于培养年轻研究人员的职业生涯，并在指导研究人员继续获得独立政府资助方面建立了良好的记录。 Edwards 博士获得了无数荣誉，包括 2006 年 IDSA 年度导师奖、2008 年当选医学研究所成员以及 2011 年被儿科传染病学会评选为年度杰出医师。此外，范德比尔特大学医学中心为年轻研究人员的研究和培训提供了丰富的环境，并通过临床和转化科学家发展办公室对所有受指导的医师科学家进行集中监督。 Thomsen 博士的长期目标是成为一名独立资助的医师科学家，在葡萄球菌免疫研究中架起人类和实验室研究的桥梁，最终确定预防和治疗金黄色葡萄球菌的新靶点。本提案中详细介绍的强有力的指导、额外的培训和环境将使他最终实现这一目标。该研究提案扩展了候选人之前发表的关于儿科葡萄球菌定植和疾病中宿主和病原体相互作用的工作。金黄色葡萄球菌无害地寄生在近 1/3 人口的前鼻孔中，但会导致某些人出现严重的侵袭性疾病。人们对控制这种关系的因素知之甚少，这仍然是预防和治疗药物开发的障碍。该候选人最近对患有侵袭性葡萄球菌病的儿童进行的研究得出了有关中和抗体对最近描述的一种重要毒素 LukAB 的反应的新发现。拟议的工作重点是假设针对这种毒素的高水平、功能性抗体反应可以预防侵袭性或复发性金黄色葡萄球菌疾病的发展。 在目标 1 中，候选人将开发具有金黄色葡萄球菌感染四种主要表型（定植、皮肤感染、复发性皮肤感染和侵袭性疾病）中每一种的儿童的前瞻性队列，并检查这些儿童中的抗葡萄球菌抗体谱。随着时间的推移，队列，导致特定抗体滴度和临床疾病特征之间的相关性。在目标 2 中，完善的功能性抗体测定将能够确定抗体功能（预防葡萄球菌外毒素引起的中性粒细胞裂解）以及这种中和活性与临床表型的相关性。在目标 3 中，候选人将扩展其开发针对 LukAB 的人源单克隆抗体的工作。通过确定抗 LukAB 抗体针对毒素每个亚基的结合和中和能力，将获得对人类金黄色葡萄球菌疾病后天然存在的抗 LukAB 抗体的细胞保护作用机制的新见解。这项工作的主要合作者包括范德比尔特大学世界著名免疫学家、人类单克隆抗体专家 James Crowe 博士和纽约大学医学院 Victor Torres 博士，他是葡萄球菌发病机制和 S 领域公认的专家。 .金黄色葡萄球菌外毒素。该项目将增进对金黄色葡萄球菌定植和疾病的抗体反应的了解，并将研究特定葡萄球菌毒力因子作为未来疫苗或新型治疗剂靶标的潜力。