"Genetic Approaches for Improving Tuberculosis Vaccines"

“改进结核病疫苗的基因方法”

基本信息

批准号：
8049832
负责人：
WILLIAM Robert JACOBS
金额：
$ 38.07万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/8049832
关键词：
Antigens Antioxidants Apoptosis Apoptotic Area Attenuated Attenuated Vaccines Badger Cattle Cell Line Characteristics Commit Data Deer Defect Development Engineering Genes Genetic Genetic Screening Genus Mycobacterium Glycolipids Goals Green Fluorescent Proteins Growth HIV Human Human Development Immune Immune response Immunity Immunocompromised Host Infant Infection Interleukin-12 Libraries Life Modification Molecular Analysis Mus Mutation Mycobacterium smegmatis Mycobacterium tuberculosis Names Nicotinic Acids Organism Phenotype Principal Investigator Production Recombinants Risk Safety South Africa T-Lymphocyte Tuberculosis Tuberculosis Vaccines Vaccines Vertebral column Virulent aerosolized bactericidal immunity base cytokine immunogenicity improved killings macrophage microbial mouse model mutant neonate novel novel vaccines prevent programs promoter safety testing success tuberculosis immunity vaccination against tuberculosis vaccine candidate vaccine efficacy

项目摘要

An efficacious and safe vaccine is needed for Tuberculosis. The goal of this project is to develop a novel TB vaccine candidate strains of M. tuberculosis and M. smegmatis. Safety is achieved by generating attenuated mutants that fail to grow in immunocompromised mice. To generate a more efficacious TB vaccine, this project will generate mutants that have enhanced immunogenicity. Enhanced immunogenicity can be achieved by identifying mutations that inactivate determinants that evade host innate and adaptive immune responses. M. tuberculosis has the ability to actively suppress the induction of THI cytokines. Aim 1 utilizes a screen employing a macrophage cell line containing the gene encoding the green fluorescent protein fused to the IL-12 inducible promoter. Transposon and null deletion mutants of attenuated M. tuberculosis will be screened for the ability to induce IL-12. M. tuberculosis actively prevents apoptosis. Aim 2 uses a genetic screen to identify apoptotic blocking effectors (abe) mutations. The mutants isolated in both Aim 1 and Aim 2 will be evaluated for their efficacy in protecting mice against aerosolized M. tuberculosis challenges using both M. tuberculosis H37Rv and the KZN strain from South Africa. Preliminary data for Aim 3 has identified a novel set of genes in M. smegmatis named ike for innate killing evasion. The M. smegmatis Aike deletion Mice immunized with M. smegmatis Aike mutant containing a set of M. tuberculosis genes (named IKEPLUS) elicits a bactericidal immunity against M. tuberculosis. Heterologous prime and boosts with ILEPLUS and attenuated M. tuberculosis will be explored. RELEVANCE (See instmctions):

结核病需要有效且安全的疫苗。该项目的目标是开发一种新型结核病结核分枝杆菌和耻垢分枝杆菌的候选疫苗株。安全是通过生成来实现的无法在免疫功能低下的小鼠中生长的减毒突变体。产生更有效的结核病疫苗，该项目将产生具有增强免疫原性的突变体。增强免疫原性可以通过识别使逃避宿主先天和适应性的决定簇失活的突变来实现免疫反应。结核分枝杆菌能够主动抑制 THI 细胞因子的诱导。目的 1使用含有编码绿色荧光的基因的巨噬细胞系的筛选与 IL-12 诱导型启动子融合的蛋白质。减毒分枝杆菌的转座子和无效缺失突变体。将筛选结核病患者诱导 IL-12 的能力。结核分枝杆菌积极防止细胞凋亡。目标 2 使用基因筛选来识别细胞凋亡阻断效应 (abe) 突变。分离出的突变体将评估 Aim 1 和 Aim 2 在保护小鼠免受雾化支原体感染方面的功效。使用结核分枝杆菌 H37Rv 和来自南非的 KZN 菌株进行结核病挑战。初步的 Aim 3 的数据在耻垢分枝杆菌中发现了一组新的基因，名为 ike，用于先天杀伤逃避。这耻垢分枝杆菌艾克缺失用含有一组耻垢分枝杆菌艾克突变体免疫的小鼠。结核病基因（名为 IKEPLUS）可引发针对结核分枝杆菌的杀菌免疫力。将探索 ILEPLUS 和减毒结核分枝杆菌的异源初免和加强。相关性（参见说明）：