"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.

宿主对结核杆菌的有效免疫取决于T细胞介导的抗结核反应 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中编码 促进宿主免疫逃避或破坏，并通过以下方式干扰有效接种 活的减毒分枝杆菌菌株。在以前的工作中，我们已经确定了多个免疫逃避基因， 并且已经证明它们的失活或缺失可以导致更免疫原性的、减毒的活的 分枝杆菌疫苗在本项目中，我们将在此背景下开发新颖的活M。结核 菌株产生增强的T细胞反应和更强大的保护免疫力在感染的动物。 即使在免疫缺陷的情况下，也会引入突变来消除毒力， 创造原则上可安全广泛用于人类的疫苗株。此外， 我们将使用化学佐剂掺入活分枝杆菌疫苗株， 加强继发性应答以进一步增强疫苗诱导的抗 结核提出了三个具体目标：1）评估M突变的影响。的结核 增强感染宿主细胞对T细胞应答的凋亡; 2）鉴定和表征M. 3）将联合收割机基因修饰与 化学佐剂和加强策略，以增强T细胞应答和由 减毒M.结核病疫苗株。这些研究的长期目标是建立原则， 将导致更安全和更有效的活M。结核病疫苗将有助于控制全球 结核病的负担和减少多药耐药菌株的出现。该项目涉及到 本项目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，并通过建立相关的保护，通过分析特定的细胞 免疫反应。广泛的互动与其他组成部分的政治行动资助计划是 该项目将使sianificantiv受益于poll支持的各种核心资源。 相关性（参见说明）： 这项建议是一个计划的组成部分，旨在更详细地了解 结核分枝杆菌逃避宿主免疫而引起严重疾病的机制， mortality.研究的目标是建立原则，使设计和建设的 更好的预防结核病的疫苗。