Mechanisms of vitamin A-dependent risk for tuberculosis progression and prevention

维生素 A 依赖性结核病进展和预防风险的机制

• 批准号: 10735660
• 负责人: Brendan Podell
• 金额: $ 76.88万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735660
• 关键词: Affect; All-Trans-Retinol; Automobile Driving; BCG Vaccine; Bacille Calmette-Guerin vaccination; Biological Availability; Birth; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 pandemic; Cause of Death; Cavia; Cells; Cellular Immunity; Chronic; Clinical; Communicable Diseases; Communities; Country; Data; Detection; Development; Dietary intake; Disease; Disease Outcome; Disease Progression; Environment; Exposure to; Generations; Goals; Granuloma; Human; Image; Immune; Immune System Diseases; Immune response; Immunity; Impairment; Individual; Infection; Infection Control; Intake; Isotopes; Knowledge; Laboratories; Liver; Location; Lung; Lung immune response; Malnutrition; Measures; Mediating; Metabolic; Metabolism; Methods; Morphology; Mycobacterium tuberculosis; Neonatal; Organ; Outcome; Pathogenesis; Pathologic; Pattern; Physiological; Predisposition; Pregnancy; Prevention; Production; Publishing; Research; Risk; Risk Factors; Role; Serum; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure of parenchyma of lung; Supplementation; T cell therapy; T-Lymphocyte; Therapeutic Intervention; Tuberculosis; Vaccination; Vitamin A; Vitamin A Deficiency; clinical development; comorbidity; dietary; experimental study; guinea pig model; high risk; human mortality; human subject; immune function; in vivo; low income country; lung development; metabolomics; neonate; physiologic model; prenatal exposure; preventive intervention; programs; progression risk; prophylactic; protective efficacy; pulmonary granuloma; response; single-cell RNA sequencing; transcriptomics; tuberculosis immunity; vaccination strategy; vaccine access; vaccine failure

Project Summary Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB), is the leading cause of human mortality due to an infectious disease, outside of the COVID-19 pandemic. The limited knowledge on risk factors and comorbidities for TB progression and the mechanisms by which these promote susceptibility limits the ability to develop new prevention and treatment approaches. Recently, we published data showing a causal relationship between vitamin A deficiency and progression to clinical active TB disease, carrying up to a 10-fold higher risk for human TB progression. The substantial TB risk associated with vitamin A deficiency highlights the need to understand the mechanisms by which this molecule contributes to TB pathogenesis, particularly in the context of malnutrition among TB-affected communities, which are often the same communities affected by vitamin A deficiency. Vitamin A has been shown to have an impact on both innate and cell-mediated immunity, where diverse roles in immunity convolute the potential contributions of this molecule to TB immunity. We hypothesize that vitamin A is required for effective cell-mediated immunity to control infection after exposure, and respond properly to vaccination, requiring production within the lung for development of effective immunity. The goals of this research are to better understand the contribution of vitamin A bioavailability to the development of the immune response, the metabolic perturbations of vitamin A during infection that may limit bioavailability, and how vitamin A status impacts efficacies of BCG vaccination practices. These goals will be achieved through three Aims using a guinea pig model of vitamin A deficiency developed in our laboratory. We will first determine the contribution of vitamin A bioavailability to the development of the coordinated granuloma immune response using single cell and spatial transcriptomic approaches on infected guinea pig lung tissues. Next, we will evaluate cellular, organ-level, and systemic vitamin A metabolic patterns during infection using stable heavy isotope tracing methods in the guinea pig model throughout the course of infection. Finally, the impact of vitamin A on protective efficacy of BCG vaccination, the only vaccine available for TB, will be assessed under conditions of physiologic and pathologic neonatal vitamin A deficiencies. Upon completing these experiments, we will have determined the role of vitamin A in the development of the granuloma and cell mediated immunity, the requirements for, and availability of, vitamin A at the site of infection in the lung, and the impact of existing and proposed human vitamin A supplementation programs on the efficacy of BCG vaccination. These results will elucidate mechanisms of TB disease progression, identify the role of vitamin A in TB immunity and propose informed options for preventive or therapeutic intervention on vitamin A deficiency.

项目摘要 结核分枝杆菌（Mycobacterium tuberculosis）是结核病（Tuberculosis，TB）的病原体，是导致人类死亡的主要原因 由于感染性疾病，在COVID-19大流行之外。对风险因素的了解有限， 结核病进展的合并症及其促进易感性的机制限制了 开发新的预防和治疗方法。最近，我们公布的数据显示， 维生素A缺乏与进展为临床活动性结核病之间的关系， 人类结核病的发展。与维生素A缺乏相关的结核病风险很大，这突出表明需要 了解这种分子促进结核病发病机制的机制，特别是在 受结核病影响的社区营养不良，这些社区往往是受维生素A影响的社区 缺陷维生素A已被证明对先天免疫和细胞介导的免疫都有影响， 在免疫中的不同作用涉及该分子对TB免疫的潜在贡献。我们假设 维生素A是有效的细胞介导的免疫所必需的，以控制暴露后的感染， 适当地接种疫苗，需要在肺内产生以产生有效的免疫力。的目标 这项研究是为了更好地了解维生素A的生物利用度的发展， 免疫反应，感染期间维生素A的代谢紊乱，可能限制生物利用度，以及 维生素A状况如何影响卡介苗接种实践的效力。这些目标将通过 三个目的使用我们实验室开发的维生素A缺乏症豚鼠模型。我们将首先确定 维生素A生物利用度对协调性肉芽肿免疫反应的发展的贡献 使用单细胞和空间转录组学方法在感染的豚鼠肺组织上。接下来，我们将评估 使用稳定重同位素研究感染期间细胞、器官水平和全身维生素A代谢模式 在整个感染过程中在豚鼠模型中的追踪方法。最后，维生素A对 卡介苗接种是唯一可用于结核病的疫苗，其保护效力将在以下条件下进行评估： 生理和病理新生儿维生素A缺乏症。完成这些实验后，我们将 确定了维生素A在肉芽肿和细胞介导的免疫中的作用， 在肺部感染部位对维生素A的需求和可用性，以及现有和 提出人体补充维生素A方案对卡介苗接种效果的影响。这些结果将 阐明结核病进展的机制，确定维生素A在结核病免疫中的作用，并提出 提供关于维生素A缺乏症的预防或治疗干预的知情选择。