Evaluating the Functional Antibody Response to Pediatric S. aureus Infections

描述(由申请人提供)：这个职业发展奖的首要目标是提供一个全面的培训计划，为候选人的独立资助的翻译研究职业生涯做好准备，重点是主要细菌病原体金黄色葡萄球菌的宿主-病原体相互作用。候选人艾萨克·汤姆森博士是范德比尔特大学儿科传染病学部的儿科学助理教授 拥有以患者为中心的研究高级学位(临床调查理学硕士学位，MSCI)。这项拟议的研究直接检查了目前对人类对金黄色葡萄球菌免疫反应的理解中的关键空白。候选人的近期目标是在获得适应性免疫学和分子流行病学方面的更多专业知识的同时，继续对儿童中葡萄球菌定植和疾病的体液免疫反应的作用进行富有成效的调查。这一奖项将允许候选人履行 这一目标包括正规的研究生水平的课程工作，关键免疫学技术的研讨会，以及5年指导研究的保护。拟议的研究将在未来几年内进行，作为综合培训经验的一部分，由候选人的共同导师凯瑟琳·爱德华兹博士和巴迪·克里奇博士指导。克里奇博士是金黄色葡萄球菌研究领域的知名研究员，并于2007年获得了IDSA/Shea在MRSA研究领域的青年研究员奖和2012年PDS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著作。他将担任这个项目的“实践”、翻译科学导师。爱德华兹博士是国际公认的儿科传染病和疫苗学专家。爱德华兹博士在保持着高效的研究组合的同时，还致力于培养年轻调查人员的职业生涯，并在指导后来获得独立政府资助的调查人员方面取得了良好的记录。爱德华兹博士获得了无数荣誉，包括2006年IDSA年度最佳导师奖，2008年当选为医学研究所成员，以及2011年被儿科传染病学会选为年度杰出医生。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内科科学家进行集中监督。汤姆森博士的长期目标是成为一名独立资助的内科科学家，将葡萄球菌免疫研究中的人类研究和实验室研究联系起来，最终确定预防和治疗金黄色葡萄球菌的新靶点。这份提案中详细说明的强有力的指导、额外的培训和环境将使他最终实现这一目标。这项研究提案扩展了候选人先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。金黄色葡萄球菌对近1/3的人口的前鼻孔无损害，但在一些人会导致严重的侵袭性疾病。支配这种关系的因素知之甚少，这仍然是开发预防和治疗药物的障碍。这位候选人最近在患有侵袭性葡萄球菌疾病的儿童中所做的工作，导致了关于对一种最近被描述的重要毒素LukAB的中和抗体反应的新发现。拟议的工作集中在这样的假设上，即针对这种毒素的高水平、功能性抗体反应对侵袭性或复发的金黄色葡萄球菌疾病具有保护作用。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、反复皮肤感染和侵袭性疾病)中每一种的儿童的预期队列，并将随着时间的推移检查这些队列中的抗葡萄球菌抗体谱，导致特定抗体滴度与临床疾病特征之间的相关性。在目标2中，成熟的功能性抗体分析将允许确定抗体功能(防止葡萄球菌外毒素引起的中性粒细胞溶解)以及这种中和活性与临床表型的相关性。在目标3中，这位候选人将扩展他在开发人源性抗LukAB单抗方面的工作。通过测定抗LukAB抗体与毒素各亚基的结合和中和能力，将对金黄色葡萄球菌病后自然产生的抗LukAB抗体的细胞保护作用机制有新的认识。这项工作的主要合作者包括范德比尔特大学世界著名的免疫学家、人类单抗专家James Crowe博士，以及纽约大学医学院的Victor Torres博士，他是金黄色葡萄球菌致病机理和金黄色葡萄球菌外毒素方面的知名专家。该项目将促进对金黄色葡萄球菌定植和疾病的抗体反应的理解，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。

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.