Evaluating the Functional Antibody Response to Pediatric S. aureus Infections

描述（由申请人提供）：这个职业发展奖的总体目标是提供一个全面的培训计划，为候选人准备一个独立资助的转化研究职业生涯，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Isaac Brossen博士是范德比尔特儿科传染病部的儿科助理教授 拥有以患者为导向的研究的高级学位（临床研究科学硕士，MSCI）。这项拟议中的研究直接考察了目前对人类对S.金黄色。 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，同时继续对体液免疫反应对葡萄球菌定植和儿童疾病的作用进行富有成效的调查。该奖项将允许候选人履行 这一目标与正式的，研究生水平的课程，在关键免疫技术研讨会，并保护5年的指导研究。拟议的研究将在未来几年内进行，作为候选人的共同导师Kathryn Edwards博士和Buddy Creech博士指导下的综合培训经验的一部分。Creech博士是S.他是MRSA研究的IDSA/SHEA青年研究者奖（2007年）和2012年PIDS青年研究者奖的获得者。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“动手”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。在保持高生产力的研究组合的同时，爱德华兹博士还致力于培养年轻研究人员的职业生涯，并为指导那些继续获得独立政府资助的研究人员建立了良好的记录。爱德华兹博士获得了许多荣誉，包括2006年IDSA年度导师奖，2008年入选医学研究所，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集中监督所有受指导的医生科学家。 Dr. Rewsen的长期目标是成为一名独立资助的医生-科学家，在葡萄球菌免疫研究中连接人体和实验室研究，最终确定预防和治疗S.金黄色。强有力的指导，额外的培训，以及本提案中详细介绍的环境将使他最终实现这一目标。该研究计划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。S.金黄色葡萄球菌无害地定植在近1/3人口的前鼻孔中，但在一些人中导致严重的侵袭性疾病。管理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。候选人最近在侵袭性葡萄球菌疾病儿童中的工作导致了关于中和抗体对一种重要的，最近描述的称为LukAB的毒素的反应的新发现。这项工作的重点是假设高水平的，功能性的抗体反应，对这种毒素是保护发展的侵袭性或复发性S。金黄色葡萄球菌病 在目标1中，候选人将开发具有S的四种主要表型中的每一种的儿童的前瞻性队列。金黄色葡萄球菌感染（定植，皮肤感染，复发性皮肤感染和侵袭性疾病），并将检查这些队列中随时间推移的抗葡萄球菌抗体谱，导致特异性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允许测定抗体功能（在预防葡萄球菌外毒素引起的中性粒细胞溶解中）以及该中和活性与临床表型的相关性。在目标3中，该候选人将扩展他的工作，开发针对LukAB的人源性单克隆抗体。通过测定抗LukAB抗体对毒素各亚基的结合和中和能力，将获得对天然存在的抗LukAB抗体在S.金黄色葡萄球菌病这项工作的主要合作者包括范德比尔特世界著名的免疫学家、人类单克隆抗体专家James Crowe博士和纽约大学医学院的维克托托雷斯博士，他是葡萄球菌发病机制和S.金黄色葡萄球菌外毒素该项目将促进对S.金黄色葡萄球菌定植和疾病，并将检查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点的潜力。

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.