Mycobacterial determinants of escape from pathogen-specific immunity

项目总结/摘要 该提案提出了一个5年的分枝杆菌研究和职业发展计划 结核候选人Allison Carey，医学博士，博士，目前是美国医学会病理学临床研究员。 马萨诸塞州总医院的医生，在Sarah博士的指导下开始了博士后研究 在哈佛T. H的财富。公共卫生学院。拟议的职业发展计划包括 结构化的培训计划，为凯里博士提供成为一名独立调查员的技能， 一个学术医疗中心，研究重点是结核分枝杆菌（Mtb）， 全球性的重大疾病，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，正式的课程，研讨会，并在先进的实践培训 实验室技术。她的导师Sarah Fortune博士是结核病研究领域公认的领导者， 培训成功的年轻科学家，科学咨询委员会的成员提供以下方面的专门知识： 研究项目的各个方面。哈佛大学的科学环境。禅宗 公共卫生是非常强大的，并嵌入在大波士顿科学界， 提供了无数的科学和职业发展资源。研究计划建立在候选人的 以前的科学培训经典果蝇遗传学和临床微生物学，并侧重于 结核分枝杆菌免疫逃避的细菌决定因素。尽管有有效的抗生素治疗方案， 部分原因是先前未感染结核分枝杆菌或接种卡介苗 (BCG)以充分保护免受随后的感染或疾病，即使强大的免疫反应， 生成的.人们对细菌的特征知之甚少，这些特征有助于在面对病原体特异性 免疫反应该候选人最初的博士后工作证明了遗传多样性是如何 存在于Mtb临床菌株之间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 当免疫致敏的宿主暴露于Mtb时，在目标1中，比较基因组学和候选基因 将采用各种方法来确定再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，来自迅速扩大的“北京”亚系的结核分枝杆菌菌株更有可能是 逃避卡介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，将使用功能基因组学方法TnSeq来鉴定细菌必需的基因 在引发免疫反应的环境中生存和生长。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， 为候选人提供独立研究的途径。

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.