Mycobacterial determinants of escape from pathogen-specific immunity

分枝杆菌逃避病原体特异性免疫的决定因素

• 批准号: 9583677
• 负责人: Allison Carey
• 金额: $ 20.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-14 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9583677
• 关键词: Academic Medical Centers; Address; Advisory Committees; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Award; BCG Live; BCG Vaccine; Bacteria; Bacterial Genes; Boston; Candidate Disease Gene; Cessation of life; Clinical; Clinical Microbiology; Communities; Data; Development; Development Plans; Disease; Doctor of Philosophy; Drosophila genus; Environment; Exhibits; Exposure to; Failure; Fortune; Foundations; Future; General Hospitals; Genes; Genetic; Genetic Determinism; Genetic Variation; Genomic approach; Genomics; Goals; Growth; Heterogeneity; Human; Immune; Immune Evasion; Immune response; Immunity; Immunologics; Individual; Infection; Integration Host Factors; Investigation; Knowledge; Laboratories; Libraries; Massachusetts; Mentors; Mentorship; Molecular Genetics; Morbidity - disease rate; Mycobacterium tuberculosis; Outcome; Pathology; Pathway interactions; Phenotype; Population; Postdoctoral Fellow; Primary Infection; Public Health Schools; Recording of previous events; Regimen; Research; Research Personnel; Research Project Grants; Research Proposals; Resource Development; Scientist; Structure; Techniques; Testing; Training; Training Programs; Tuberculosis; Vaccination; Vaccines; Variant; Virulence; Work; adaptive immune response; bacterial genetics; career; career development; clinically relevant; comparative genomics; computerized tools; defined contribution; density; epidemiology study; experimental study; functional genomics; gene discovery; genetic approach; genetic variant; global health; immunogenicity; immunoregulation; inflammatory milieu; insight; member; microbial; mortality; mouse model; mutant; mycobacterial; novel therapeutics; novel vaccines; pathogen; pressure; public health intervention; research and development; secondary infection; skills; success

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.

项目摘要/摘要 本提案提出了分枝杆菌研究的五年研究和职业发展计划。 肺结核。候选人艾莉森·凯里，医学博士，目前是美国国立卫生研究院病理学临床研究员 马萨诸塞州总医院在萨拉博士的指导下开始了博士后研究 哈佛大学公共卫生学院的《财富》杂志。拟议的职业发展计划包括 有组织的培训计划，为凯里博士提供成为一名独立调查员的技能 学术医学中心，重点研究结核分枝杆菌(Mtb)，该病的病原体 具有全球意义的疾病--结核病。她将在她的指导下实现这一职业目标 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。她的导师萨拉·福琼博士是结核病研究领域的知名领导者，有 培养成功的青年科学家，科学咨询委员会成员提供专业知识 建议的研究项目的每一个方面。哈佛大学陈德熙学院的科学环境 公共卫生非常强大，并植根于大波士顿科学界，该科学界 提供无数的科学和职业发展资源。研究建议建立在候选人的基础上 之前在经典果蝇遗传学和临床微生物学方面的科学培训，并专注于 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方案，但全球结核病的负担 居高不下的部分原因是之前没有感染结核杆菌或接种卡介苗 (卡介苗)以充分预防后续感染或疾病，即使强大的免疫反应是 已生成。对于在病原体面前促进生存的细菌特征，人们知之甚少。 免疫反应。这位候选人最初的博士后工作证明了基因多样性是如何 结核分枝杆菌临床菌株的存在会影响对抗生素的敏感性和抗生素耐药性的出现。 在这里，候选人试图调查包括菌株多样性在内的细菌特征如何决定结果。 当免疫启动的宿主暴露于结核分枝杆菌。目标1，比较基因组学和候选基因 将使用方法来确定在再次感染期间成功的细菌遗传决定因素。一些人 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 为了逃避卡介苗疫苗提供的免疫力，这一假说将在AIM 2中进行实验验证。 在目标3中，将使用一种名为TnSeq的功能基因组学方法来识别至关重要的细菌基因 在启动免疫反应的背景下生存和生长。这些目标的结果将会回答 该领域的基本问题，通报新疗法和疫苗的发展，并公开 为候选人提供独立研究的途径。