Mycobacterial determinants of escape from pathogen-specific immunity

项目概要/摘要 该提案提出了分枝杆菌研究的 5 年研究和职业发展计划 结核病。候选人艾莉森·凯里 (Allison Carey)，医学博士、哲学博士，目前是病理学临床研究员 麻省总医院在Sarah博士的指导下开始博士后研究 哈佛 T.H. 财富陈公共卫生学院。拟议的职业发展计划包括 结构化培训计划，为凯里博士提供成为独立调查员的技能 学术医疗中心，重点研究结核分枝杆菌 (Mtb)，它是结核病的病原体 全球重大疾病——结核病（TB）。她将通过她的指导实现这一职业目标 导师、科学咨询委员会、正式课程、研讨会和高级实践培训 实验室技术。她的导师 Sarah Fortune 博士是结核病研究领域的知名领导者，拥有悠久的历史 培训成功的年轻科学家，科学顾问委员会成员提供以下方面的专业知识 拟议研究项目的各个方面。哈佛 T.H. 的科学环境陈氏学院 公共卫生非常强大，并且融入了大波士顿科学界， 提供无数的科学和职业发展资源。该研究计划建立在候选人的基础上 之前接受过经典果蝇遗传学和临床微生物学的科学培训，重点关注 Mtb 免疫逃避的细菌决定因素。尽管有有效的抗生素治疗方案，全球结核病负担 居高不下的部分原因是先前感染结核分枝杆菌或接种卡介苗失败 （卡介苗）以充分防止随后的感染或疾病，即使强大的免疫反应是 生成的。对于细菌在面对特定病原体时有利于生存的特征知之甚少 免疫反应。该候选人最初的博士后工作已经证明了遗传多样性如何 Mtb 临床菌株中存在的 Mtb 会影响抗生素敏感性和抗生素耐药性的出现。 在这里，候选人试图研究包括菌株多样性在内的细菌特征如何决定结果 当免疫引发的宿主暴露于 Mtb 时。目标1，比较基因组学和候选基因 方法将用于确定再次感染期间成功的细菌遗传决定因素。一些 流行病学研究表明，来自迅速扩张的“北京”亚系的结核分枝杆菌菌株更有可能 逃避 BCG 疫苗接种提供的免疫力，这一假设将在目标 2 中进行实验检验。 在目标 3 中，功能基因组学方法 TnSeq 将用于识别重要的细菌基因 在免疫反应启动的情况下生存和生长。这些目标的结果将回答 该领域的基本问题，为新疗法和疫苗的开发提供信息，并开放 候选人独立研究的途径。

PROJECT SUMMARY/ABSTRACT This proposal presents a 5-year research and career development plan in the study of Mycobacterium tuberculosis. The candidate, Allison Carey, MD, PhD, is currently a clinical fellow in Pathology at the Massachusetts General Hospital who has begun postdoctoral research under the mentorship of Dr. Sarah Fortune at the Harvard T.H. Chan School of Public Health. The proposed career development plan includes a structured training program to provide Dr. Carey with the skills to become an independent investigator at an academic medical center with a research focus on Mycobacterium tuberculosis (Mtb) the causative agent of the globally significant disease, tuberculosis (TB). She will achieve this career goal through the guidance of her mentor, a scientific advisory committee, formal coursework, seminars, and hands-on training in advanced laboratory techniques. Her mentor, Dr. Sarah Fortune, is an established leader in TB research with a history of training successful young scientists, and the members of the scientific advisory committee provide expertise in each facet of the proposed research project. The scientific environment of the Harvard T.H. Chan School of Public Health is exceptionally strong, and is embedded within the greater Boston scientific community, which offers myriad scientific and career development resources. The research proposal builds on the candidate's previous scientific training in classic Drosophila genetics and clinical microbiology, and is focused on the bacterial determinants of Mtb immune evasion. Despite effective antibiotic regimens, the global burden of TB remains high in part due to the failure of prior infection with Mtb or vaccination with Bacille Calmette-Guerin (BCG) to fully protect against subsequent infection or disease, even though a robust immune response is generated. Little is known about the bacterial features that facilitate survival in the face of the pathogen-specific immune response. The candidate's initial post-doctoral work has demonstrated how the genetic diversity that exists among Mtb clinical strains impacts antibiotic susceptibility and the emergence of antibiotic resistance. Here, the candidate seeks to investigate how bacterial features including strain diversity determine outcomes when an immunologically primed host is exposed to Mtb. In Aim 1, comparative genomics and candidate gene approaches will be used to identify bacterial genetic determinants of success during reinfection. Some epidemiologic studies suggest that Mtb strains from the rapidly expanding “Beijing” sublineage are more likely to escape the immunity provided by BCG vaccination, a hypothesis that will be experimentally tested in Aim 2. In Aim 3, a functional genomics approach, TnSeq, will be used to identify the bacterial genes that are essential for survival and growth in the setting of a primed immune response. The outcome of these aims will answer fundamental questions in the field, inform the development of new therapeutics and vaccines, and open avenues of independent research for the candidate.