The Tuberculosis Granuloma

结核肉芽肿

• 批准号: 7797442
• 负责人: JOHN CHAN
• 金额: $ 32.91万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7797442
• 关键词: Antitubercular Agents; Attenuated; Bacillus (bacterium); Bacteria; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cord Factors; Defense Mechanisms; Development; Disease Outcome; Engineering; Evaluation; Exhibits; Genes; Genomics; Goals; Granuloma; Granuloma by Site; Granulomatous; Host Defense; Host Defense Mechanism; Immunization; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Laboratories; Lead; Link; Lung; Mediating; Molecular Analysis; Mus; Mycobacterium tuberculosis; Mycolic Acid; Pantothenic Acid; Pathway interactions; Play; Production; Reaction; Regulation; Role; Safety; T-Lymphocyte; Tissues; Tuberculosis Vaccines; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vaccination; Vaccines; Virulence; Virulent; attenuation; base; cyclopropane synthetase; cytokine; design; genetic analysis; immunogenicity; immunopathology; macrophage; mutant; mycobacterial; novel; programs; response; tuberculosis granuloma; tuberculosis immunity; vaccine candidate; vaccine safety

The overall goal of this Program Project is to develop novel effective and safe tuberculosis (TB) vaccine. The strategy taken is based on the results generated by the Jacobs laboratory, indicating that safe and effective TB vaccines can be derived from virulent Mycobacterium tuberculosis (Mtb): immunization with the markedly attenauted deltaRD1delta-panCD Mtb (generated by disruption of the a 10-kb genomic region called RD1 and the pantothenic acid biosynthetic genes, panC and panD) protects CD4 T cell-deficient mice against challenge with virulent bacilli in a CD8 T cell-independent manner. The granuloma plays a significant role in host defense against Mtb. Interaction between the host and the bacillus in the granuloma determines disease outcome and/or tissue-damaging immnunopathology, an undesirable feature of vaccine candidate in terms of safety that is caused by tumor necrosis factor (TNF). Understanding the host granulomatous response will help guide the design of anti-TB interventions including vaccines. Project 3 will direct efforts at i) characterizing the granulomatous response elicited by the Mtb mutant vaccines; ii) isolating mutants of the tubercle bacillus with diminished capacity to induce macrophage TNF production, so as to identify genes whose disruption will cause attenuated Mtb immunopathogenicity and therefore, enhances vaccine safety; iii) examining the granulomatous reaction of deltaRD1delta-panCD-immunized CD4-deficient mice, developed in response to challenge with virulent Mtb. We believe these studies will generate information that will guide the design of safer and more effective TB vaccines, and reveal novel host defense and immunopathologic mechanisms involved in tuberculous infection.

该计划项目的总体目标是开发新型有效且安全的结核病（TB） 疫苗。采取的策略是基于雅各布实验室产生的结果，表明可以从有毒的结核分枝杆菌（MTB）中得出安全有效的TB疫苗：与明显的deltard1deltaDelta-Pancd MTB免疫接种（MTB），由deltard1delta-pancd MTB（由A 10-kb Genomic Regant coiss coiss coiss coiss and perth perth perth perth perth and pant rd1和pant rd rd rd1和pant rd rd rd rd rd rd and pant rd rd rd rd rd rd and pant rd rd rd1产生Pand）保护CD4 T细胞缺陷小鼠以CD8 ​​T细胞无关的方式免受毒性杆菌的挑战。肉芽瘤在对MTB的宿主防御中起着重要作用。颗粒瘤中宿主与芽孢杆菌之间的相互作用决定了疾病的结果和/或组织受损的IMMNOPAROGY，这是疫苗候选者在安全性方面的不良特征，这是由肿瘤坏死因子（TNF）引起的。了解宿主的肉芽肿反应将有助于指导包括疫苗在内的抗TB干预措施的设计。项目3将指导i）表征MTB突变疫苗引起的肉芽肿反应； ii）分离结核芽孢杆菌的突变体，其能力降低了诱导巨噬细胞TNF产生的能力，以鉴定其破坏会导致MTB免疫发育性减弱的基因，从而增强疫苗安全； iii）检查了Deltard1delta-PANCD免疫的CD4缺陷小鼠的肉芽肿反应，这些小鼠是为了响应毒性MTB的挑战而开发的。我们认为这些研究将产生信息，以指导更安全，更有效的结核病疫苗的设计，并揭示新型宿主 涉及结核病感染的防御和免疫病理机制。