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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

基本信息

批准号：
10425462
负责人：
Allison Carey
金额：
$ 19.87万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10425462
关键词：
Academic Medical Centers Address Advisory Committees Antibiotic susceptibility Antibiotics Award BCG Live BCG Vaccine Bacille Calmette-Guerin vaccination 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 emerging antibiotic resistance 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 transposon sequencing

项目摘要

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.

项目总结/文摘