Immune Correlates of Protection from TB

结核病防护的免疫相关性

基本信息

批准号：
9513405
负责人：
Deepak Kaushal
金额：
$ 130.13万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9513405
关键词：
Address Adult Aerosols Animals Antibodies Antigens Antioxidants Attenuated B-Lymphocytes BCG Vaccine Bar Codes Biological Models Biopsy Bronchi Bronchus-Associated Lymphoid Tissue CD4 Positive T Lymphocytes Cells Cessation of life Clinical/Radiologic Collection Data Development Dose Escape Mutant Evolution Exhibits Failure Genus Mycobacterium Granuloma HIV Human Humoral Immunities Immune Immune response Immunity Immunize Infection Life Cycle Stages Lung MS4A1 gene Macaca Macaca mulatta Maintenance Measurement Measures Memory Microdissection Modeling Mucous Membrane Mus Mycobacterium tuberculosis Oxidation-Reduction Pathology Phenotype Play Production Pulmonary Pathology Pulmonary Tuberculosis Reagent Regulation Regulon Role Route SIV Series Specificity Stains Stress T cell response T-Cell Depletion T-Lymphocyte Techniques Testing Tissues Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccines Virulence Virulence Factors Virus bactericide biological adaptation to stress co-infection cytokine enzyme linked immunospot assay experimental study innovation insight microbial mortality mucosal vaccination mutant novel novel vaccines pathogen protective efficacy recruit response stem transcriptome sequencing tuberculosis immunity vaccine candidate

项目摘要

Abstract. Since TB remains an infection that results in extensive mortality, efficacious vaccines against Mtb infection are urgently sought. Recently, it has been proposed that mycobacteria attenuated in the regulation of redox-stress may be effective vaccine candidates, since these could interfere with the production of several microbial antioxidants. We have recently shown that an isogenic Mtb mutant in stress-response factor SigH significantly and impressively protects against homologous Mtb infection if used to immunize macaques via the aerosol route. As part of this application we propose to better understand correlates of protective immunity upon mucosal vaccination with sigH, using a set of three specific aims that are not inter-dependent. In addition we will study if such vaccination can also protect against infection with highly infectious heterologous strains of Mtb (Specific Aim 1). In a series of mechanistic experiments, we will deplete B-cells recruited to the lung iBALT follicles in great numbers following vaccination with the sigH mutant, using a recently developed and optimized macaque-specific reagent. These animals will be concurrently challenged with a high-dose homologous Mtb challenge to assess if the protective efficacy of sigH is eviscerated in the absence of B-cells (Specific Aim 2). Finally, we will study if inducible bronchus associated tissue (iBALT) provides a sanctuary where SIV can persist, or whether iBALT protects Tfh cells from depletion by SIV during co-infection (Specific Aim 3). Together the results obtained as part of these three aims will i) have the potential to establish sigH as a leading live-mycobacterium anti-TB vaccine vehicle; ii) provide defining correlates of protection from TB in a model system which would provide immediate applicability in human trials; and iii) define the controversial role of B-cells in protection from TB.

抽象的。由于结核病仍然是一种感染，导致广泛的死亡率，因此对MTB的有效疫苗迫切需要感染。最近，有人提出分枝杆菌在调节中减弱氧化还原应力可能是有效的疫苗候选者，因为这些可能会干扰几种的生产微生物抗氧化剂。我们最近表明，应力反应因子中的同基因MTB突变体叹气如果用来通过猕猴免疫猕猴，可以显着和令人印象深刻的气溶胶路线。作为本应用的一部分，我们建议更好地了解粘膜上受保护免疫的相关性使用不依赖性的三个特定目的的疫苗接种，使用Sigh。另外，我们将学习如果这种疫苗接种也可以防止具有高度感染性异源菌株MTB的感染（特定目标1）。在一系列机械实验中，我们将销毁在肺部卵泡中招募的B细胞使用最近开发和优化的疫苗之后的大量疫苗接种疫苗猕猴特异性试剂。这些动物将与高剂量同源MTB同时挑战在没有B细胞的情况下，要评估受保护效率的挑战是否会被剔除（特定的AIM 2）。最后，我们将研究诱导型支气管相关组织（IBALT）是否提供SIV可以提供的避难所持续存在，或者IBALT是否保护TFH细胞在共同感染过程中免受SIV耗竭的影响（特定AIM 3）。作为这三个目标的一部分获得的结果将i）有可能建立 领先的活菌群抗TB疫苗车； ii）在A中提供针对TB保护的定义相关性模型系统将立即在人体试验中适用； iii）定义有争议的角色 B细胞免受结核病保护。