"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.

宿主对结核分枝杆菌的有效免疫取决于 T 细胞介导的针对杆菌抗原的反应。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，并且这些途径干扰活的减毒分枝杆菌菌株的有效疫苗接种。在之前的工作中，我们已经鉴定了多个免疫逃避基因，并证明它们的失活或缺失可以产生更具免疫原性的减毒活分枝杆菌疫苗。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菌株，这些菌株可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。即使在免疫缺陷的情况下，还将引入突变以消除毒力，从而创造出原则上可以安全地在人群中广泛使用的疫苗株。此外，我们将在活分枝杆菌疫苗株中加入化学佐剂，并采用多种方法来增强继发反应，以进一步增强疫苗诱导的结核病保护作用。提出了三个具体目标： 1) 评估结核分枝杆菌中增强受感染宿主细胞凋亡的突变对 T 细胞反应的影响； 2) 鉴定和表征增强 MHC 11 类抗原呈递的结核分枝杆菌突变体； 3) 将基因修饰与化学佐剂和加强策略相结合，以增强结核分枝杆菌减毒疫苗株诱导的T细胞反应和保护功效。这些研究的长期目标是建立更安全、更有效的结核分枝杆菌活疫苗的原则，从而有助于控制全球结核病负担并减少多重耐药菌株的出现。该项目通过寻求提高结核分枝杆菌减毒活疫苗的免疫原性，并通过分析特定的细胞免疫反应建立保护的相关性，与该计划项目的总体目标相关。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。