Effects of mycobacterial infections induced cell death on host immune response

分枝杆菌感染诱导细胞死亡对宿主免疫反应的影响

基本信息

批准号：
8046730
负责人：
Sunhee Lee
金额：
$ 23.55万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-03 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8046730
关键词：
Aerosols Alveolar Macrophages Antigens Apoptosis Apoptotic Attenuated Vaccines Autophagocytosis Bacillus (bacterium)Bacterial Infections Biological Preservation Cell Communication Cell Death Cell Death Induction Cell Death Inhibition Cell Death Signaling Process Cell Survival Cells Cessation of life Chronic Complex Cytolysis Data Development Drug Delivery Systems Environment Equilibrium Failure Genes Genetic Genome Genus Mycobacterium Goals Grant Growth Host Defense Immune Immune response Immunity Immunotherapy Infection Knowledge Lead Libraries Lung Mediating Metalloproteases Molecular Mus Mutation Mycobacterium Infections Mycobacterium tuberculosis Necrosis Pathway interactions Phagocytosis Phagosomes Phenotype Process Regulation Reporting Research Research Personnel Resources Role Screening procedure Signal Pathway Signal Transduction Signal Transduction Pathway Source Tuberculosis Tuberculosis Vaccines Vaccines Vesicle Virulence Virulent adaptive immunity attenuation base immunogenicity improved innovation insight killings loss of function macrophage microbicide mortality mutant mycobacterial novel strategies pathogen prevent tool trafficking trait tuberculosis drugs vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): Cell death pathways are central to the interaction between pathogenic mycobacteria and host macrophages. The inhibition of cell death of infected host cells is a well-documented, but poorly understood, action of pathogenic mycobacteria. Mycobacteria may accrue several advantages as a result of delaying or inhibiting macrophage cell death, including preservation of a protected growth environment, engagement of intrinsic microcidal activities in the host cell, and optimal stimulation of protective immunity. The genetic basis for this anti-cell death phenotype has not been fully demonstrated or elucidated. Using a Mycobacterium tuberculosis transposon mutant library, we have screened pro-cell death mutants of M. tuberculosis and were able to find multiple genetic loci that are responsible for inhibiting infection-induced cell death of macrophages. This grant proposes to study several of these genes to examine their correlation to virulence and immunogenicity. Additionally, this study will characterize key genetic components of this important virulence trait of mycobacteria, while providing insight and tools necessary to investigate the details of this complex host-pathogen interaction. Our studies may also provide novel approaches for improving mycobacterial vaccines and identifying new TB drug targets. PUBLIC HEALTH RELEVANCE: We propose to study pro-cell death mycobacterial mutants that may enhance priming of adaptive immunity. The results of the study will be useful for the development of new drug targets and TB vaccine candidates.

描述（由申请人提供）：细胞死亡途径是致病性分枝杆菌和宿主巨噬细胞之间相互作用的核心。抑制受感染宿主细胞的细胞死亡是病原分枝杆菌的一种有据可查但了解甚少的作用。由于延迟或抑制巨噬细胞死亡，分枝杆菌可能会产生多种优势，包括保护受保护的生长环境、参与宿主细胞的内在杀微生物活性以及最佳刺激保护性免疫。这种抗细胞死亡表型的遗传基础尚未得到充分证明或阐明。使用结核分枝杆菌转座子突变体库，我们筛选了结核分枝杆菌的促细胞死亡突变体，并能够找到负责抑制感染诱导的巨噬细胞细胞死亡的多个基因位点。这笔赠款提议研究其中的几个基因，以检查它们与毒力和免疫原性的相关性。此外，这项研究将表征分枝杆菌这一重要毒力特征的关键遗传成分，同时提供研究这种复杂的宿主-病原体相互作用的细节所需的见解和工具。我们的研究还可能为改进分枝杆菌疫苗和确定新的结核病药物靶点提供新方法。公共健康相关性：我们建议研究可能增强适应性免疫启动的促细胞死亡分枝杆菌突变体。该研究结果将有助于开发新的药物靶点和候选结核病疫苗。