"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: 8871648
• 负责人: Steven A Porcelli
• 金额: $ 7.17万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871648
• 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; Population; Prevention; Production; Protein Subunits; Research; Resources; 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; screening; tuberculosis immunity; vaccine candidate; vaccine-induced immunity

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 vaccination 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 protective 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 populations. In addition, we will use the incorporation of chemical adjuvant 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 adjuvant 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 effective 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 P01 funded program are proposed, and the project will benefit significantly from the various core resources supported by the P01.

有效的宿主对结核分枝杆菌的免疫依赖于T细胞介导的针对杆菌抗原的应答。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逃避或破坏宿主免疫的途径，这些途径干扰减毒活分枝杆菌菌株的有效接种。在以前的工作中，我们已经确定了多个免疫逃避基因，并已证明，他们的失活或删除可以导致更多的免疫原性，减毒活分枝杆菌疫苗。在本项目中，我们将在此背景下开发新颖的活M。结核菌株在受感染的动物中产生增强的T细胞应答和更强大的保护性免疫。还将引入突变以消除甚至在免疫缺陷情况下的毒力，从而产生原则上可安全地在人群中广泛使用的疫苗株。此外，我们将使用化学佐剂掺入活分枝杆菌疫苗株和几种方法来加强二次应答，以进一步增强疫苗诱导的抗结核保护。提出了三个具体目标：1）评估M突变的影响。结核分枝杆菌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）将联合收割机遗传修饰与化学佐剂和加强策略相结合，以增强减毒M.结核病疫苗株。这些研究的长期目标是建立原则，这将导致更安全，更有效的活M。因此，我们需要开发新的结核病疫苗，这将有助于控制全球结核病负担和减少耐多药菌株的出现。本项目涉及本项目的总体目标，即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。建议与P01资助计划的其他组成部分进行广泛的互动，该项目将从P01支持的各种核心资源中受益匪浅。