"Determinants of T Cell Immunity to Tuberculosis Vaccines"

“T细胞对结核疫苗免疫的决定因素”

• 批准号: 8049854
• 负责人: Steven A Porcelli
• 金额: $ 37.35万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049854
• 关键词: Adjuvant; Animals; Antigen Presentation; Antigens; Apoptosis; Apoptotic; Attenuated; B-Lymphocytes; Bacillus (bacterium); CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chemicals; Core Facility; Cosmids; Development; Disease; Funding; Genes; Genetic; Genetic screening method; Genome; Goals; Growth; Human; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; In Vitro; Instruction; Lead; Life; MHC Class II Genes; Mediating; Modification; Molecular Analysis; Multi-Drug Resistance; Mutagenesis; Mutation; Mycobacterium smegmatis; Mycobacterium tuberculosis; Pathway interactions; Phagocytes; Prevention; Principal Investigator; Production; Protein Subunits; Research; Resources; Screening procedure; Specificity; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; TNF gene; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Vertebral column; Virulence; Work; auxotrophy; cytokine; design and construction; immunogenic; immunogenicity; improved; in vivo; mortality; mutant; mycobacterial; novel; novel vaccines; overexpression; programs; protective efficacy; resistant strain; response; tuberculosis immunity; vaccine candidate

Effective host immunity to Mycobacterium tuberculosis is dependent on T cell-mediated responses against antigens of the bacillus. Our recent work has shown that M.tuberculosis encodes In its genome pathways that promote evasion or subversion of host immunity, and that these interfere with effective vaccinafion by live, attenuated mycobacterial strains. In previous work, we have identified multiple immune evasion genes and have demonstrated that their inactivation or deletion can lead to more immunogenic, attenuated live mycobacterial vaccines. In this project, we will build on this background to develop novel live M. tuberculosis strains that generate enhanced T cell responses and more robust protecfive immunity in infected animals. Mutations will also be introduced to eliminate virulence even in the setting of immunodeficiency, thus creating vaccine strains that will in principle be safe for widespread use in human populafions. In addifion, we will use the incorporation of chemical adjuvants into live mycobacterial vaccine strains and several approaches to boosting of secondary responses to further enhance vaccine-induced protection against tuberculosis. Three specific aims are proposed: 1) Assess the impact of mutations In M. tuberculosis that enhance apoptosis of infected host cells on T cell responses; 2) Identify and characterize mutants of M. tuberculosis that enhance antigen presentation by MHC class 11; 3) Combine genetic modifications with chemical adjuvants and boosting strategies to enhance T cell response and protective efficacy induced by attenuated M. tuberculosis vaccine strains. The long term goal of these studies is to establish principles that will lead to safer and more effecfive live M. tuberculosis vaccines that will contribute to controlling the global burden of tuberculosis and to reducing the emergence of multidrug resistant strains. This project relates to the overall goals of this program project by seeking to improve the immunogenicity of live attenuated M. tuberculosis vaccines, and by establishing correlates of protection through the analysis of specific cellular immune responses. Extensive interactions with other components of the POl funded program are proposed, and the project will benefit sianificantiv from the various core resources supported bv the POl. RELEVANCE (See instructions): This proposal is an integral component of a program that aims to understand in greater detail the mechanisms by which Mycobacterium tuberculosis evades host immunity to cause serious disease and mortality. The goal of the research is to establish principles that will enable the design and construction of better vaccines for the prevention of tuberculosis.

有效的宿主对结核分枝杆菌的免疫力取决于T细胞介导的反应 芽孢杆菌的抗原。我们最近的工作表明，大结核病在其基因组途径中编码 促进宿主免疫的逃避或颠覆 活着，减弱分枝杆菌菌株。在以前的工作中，我们已经确定了多个免疫逃避基因 并证明它们的失活或删除会导致更多的免疫原性，衰减 分枝杆菌疫苗。在这个项目中，我们将在此背景下建立发展小说的结核病。 在感染动物中产生增强的T细胞反应和更强大的蛋白质免疫的菌株。 即使在免疫缺陷的情况下，也将引入突变以消除毒力，因此 产生原则上可以安全地使用人群中的疫苗菌株。中添， 我们将使用化学佐剂掺入活的分枝杆菌疫苗菌株和几种 提高继发反应以进一步增强疫苗诱导的保护的方法 结核。提出了三个具体目的：1）评估突变在结核分枝杆菌中的影响 增强感染宿主细胞在T细胞反应上的凋亡； 2）识别和表征M的突变体。 结核病增强了MHC 11级抗原表现； 3）将遗传修饰与 化学佐剂和增强策略以增强T细胞反应和保护性疗效 结核分枝杆菌疫苗菌株减毒。这些研究的长期目标是建立原则 将导致更安全，更有效的活结核病疫苗，这将有助于控制全球 结核病负担，减少多药抗性菌株的出现。这个项目与 该计划项目的总体目标是寻求改善活体减弱的免疫原性。 结核病疫苗，并通过分析特定细胞来建立保护的相关性 免疫反应。与POL资助计划的其他组件进行了广泛的互动是 拟议的，该项目将使支持POR的各种核心资源中受益。 相关性（请参阅说明）： 该建议是计划的组成部分，旨在更详细地了解 结核分枝杆菌逃避宿主免疫以引起严重疾病和的机制 死亡。该研究的目的是建立将实现设计和建设的原则 更好的疫苗预防结核病。