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; 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 结核分枝杆菌是结核病的病因（TB），是人类死亡率的主要原因 由于感染性疾病，在Covid-19-19大流行之外。关于风险因素和 结核病进展的合并症和这些促进易感性的机制限制了能力 开发新的预防和治疗方法。最近，我们发布了显示因果关系的数据 在维生素A缺乏和发展为临床活性结核病疾病之间，风险高10倍 用于人类结核的进展。与维生素A缺乏相关的实质性结核病风险强调了 了解该分子有助于TB发病机理的机制，尤其是在情况下 受结核病影响社区的营养不良，这些社区通常与受维生素A影响的社区相同 不足。维生素A已被证明对先天和细胞介导的免疫有影响，在那里 在免疫中的各种作用累积了该分子对结核病免疫的潜在贡献。我们假设 有效的细胞介导的免疫能够控制暴露后的感染，需要维生素A。 适当进行疫苗接种，需要在肺内产生有效免疫。目标 这项研究是为了更好地了解维生素是生物利用度对发展的贡献 免疫反应，在感染过程中维生素A的代谢扰动可能限制生物利用度和 维生素A状态如何影响BCG疫苗接种实践的功效。这些目标将通过 使用在我们的实验室中发展的维生素A缺乏症的豚鼠模型的三个目标。我们将首先确定 维生素A生物利用度对配位肉芽肿反应的发展的贡献 使用在受感染的豚鼠肺组织上的单细胞和空间转录方法。接下来，我们将评估 细胞，器官和系统性维生素A代谢模式在感染过程中使用稳定的重型同位素 在整个感染过程中，豚鼠模型中的追踪方法。最后，维生素A对 BCG疫苗接种的保护功效，是唯一可用于结核病的疫苗 生理和病理新生儿维生素A缺乏症。完成这些实验后，我们将有 确定了维生素A在肉芽肿的发展中的作用，细胞介导的免疫力，即 肺部感染部位维生素A的要求和可用性，以及现有和 提出了有关BCG疫苗接种功效的人类维生素补充计划。这些结果将会 阐明结核病疾病进展的机制，确定维生素A在结核病免疫中的作用并提出 对维生素A缺乏的预防或治疗干预的知情选择。