"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.

宿主对结核分枝杆菌的有效免疫取决于 T 细胞介导的针对结核分枝杆菌的反应 杆菌的抗原。我们最近的工作表明结核分枝杆菌在其基因组通路中编码 促进逃避或破坏宿主免疫力，并干扰有效的疫苗接种 活的减毒分枝杆菌菌株。在之前的工作中，我们已经鉴定出多个免疫逃避基因 并已证明它们的失活或缺失可以导致免疫原性更强、减毒的活病毒 分枝杆菌疫苗。在这个项目中，我们将在此背景下开发新型活结核分枝杆菌 在受感染的动物中产生增强的 T 细胞反应和更强大的保护性免疫力的菌株。 即使在免疫缺陷的情况下，也会引入突变以消除毒力，因此 创造原则上可以安全地在人类中广泛使用的疫苗株。另外， 我们将在活分枝杆菌疫苗株和几种疫苗中掺入化学佐剂 加强二次反应的方法，以进一步增强疫苗诱导的保护作用 结核。提出了三个具体目标： 1) 评估结核分枝杆菌突变的影响 增强受感染宿主细胞对 T 细胞反应的凋亡； 2) 鉴定并表征 M 的突变体。 增强 MHC 11 类抗原呈递的结核病； 3）将基因改造与 化学佐剂和增强策略，以增强 T 细胞反应和诱导的保护功效 减毒结核分枝杆菌疫苗株。这些研究的长期目标是建立以下原则： 将带来更安全、更有效的结核分枝杆菌活疫苗，这将有助于控制全球结核病 结核病负担并减少多重耐药菌株的出现。该项目涉及 该计划的总体目标是通过寻求提高减毒活支原体的免疫原性。 结核病疫苗，并通过分析特定细胞建立保护相关性 免疫反应。与 POl 资助计划的其他组成部分进行广泛的互动 该项目将受益于 POl 支持的各种核心资源。 相关性（参见说明）： 该提案是旨在更详细地了解 结核分枝杆菌逃避宿主免疫导致严重疾病的机制 死亡。研究的目标是建立能够设计和建造的原则 更好的疫苗来预防结核病。