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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要结核分枝杆菌是结核病 (TB) 的病原体，是人类死亡的主要原因由于 COVID-19 大流行之外的传染病。对风险因素和风险的了解有限结核病进展的合并症以及这些合并症促进易感性的机制限制了治疗的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维生素 A 缺乏与进展为临床活动性结核病之间存在关联，风险高达 10 倍人类结核病进展。与维生素 A 缺乏相关的巨大结核病风险凸显了以下必要性：了解该分子导致结核病发病机制的机制，特别是在这种情况下受结核病影响的社区中营养不良的情况，这些社区往往是受维生素 A 影响的社区不足。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，其中该分子在免疫中的不同作用使该分子对结核病免疫的潜在贡献变得复杂。我们假设有效的细胞介导的免疫需要维生素 A 来控制暴露后的感染并做出反应正确接种疫苗需要肺部产生有效的免疫力。的目标这项研究是为了更好地了解维生素 A 生物利用度对发育的贡献免疫反应、感染期间维生素 A 的代谢紊乱可能会限制生物利用度，以及维生素 A 状态如何影响 BCG 疫苗接种的效果。这些目标将通过三个目标是使用我们实验室开发的维生素 A 缺乏症豚鼠模型。我们首先会确定维生素 A 生物利用度对协调肉芽肿免疫反应发展的贡献对受感染的豚鼠肺组织使用单细胞和空间转录组学方法。接下来我们来评测一下使用稳定重同位素研究感染期间的细胞、器官水平和全身维生素 A 代谢模式豚鼠模型在整个感染过程中的追踪方法。最后，维生素A的影响 BCG 疫苗接种是唯一可用于结核病的疫苗，其保护效果将在以下条件下进行评估：新生儿维生素A的生理性和病理性缺乏。完成这些实验后，我们将得到确定了维生素 A 在肉芽肿和细胞介导的免疫发展中的作用，肺部感染部位维生素 A 的需求和可用性，以及现有和现有的影响提出人体维生素A补充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 在结核免疫中的作用，并提出建议维生素 A 缺乏症的预防或治疗干预的明智选择。