Modulation of immunity to tuberculosis through vitamin A-dependent nuclear receptors

通过维生素 A 依赖性核受体调节结核病免疫力

• 批准号: 9894731
• 负责人: Brendan Podell
• 金额: $ 22.8万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894731
• 关键词: Affect; Agar; Agonist; All-Trans-Retinol; Alveolar Macrophages; Antibiotic Therapy; Binding; Bone Marrow; Cause of Death; Cavia; Cell model; Cells; Cellular Immunity; Clinical; Colony-forming units; Communicable Diseases; Communities; Detection; Development; Diet; Dimerization; Disease; Disease Outcome; Disease Progression; Enzymes; FDA approved; Family; Flow Cytometry; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Gold; Growth; Immune; Immune System Diseases; Immune response; Impairment; Infection; Infection Control; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Ligands; Lung; Malnutrition; Measures; Metabolism; Modeling; Mycobacterium tuberculosis; Natural Immunity; Nuclear Family; Nuclear Receptors; Outcome; Outcome Measure; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Pharmaceutical Preparations; Play; Population; Predisposition; Prevention; RXR; Research; Risk; Risk Factors; Role; Serum; Severity of illness; Signal Transduction; Stains; Techniques; Transcription Coactivator; Transcriptional Activation; Tretinoin; Tuberculosis; Vitamin A; Vitamin A Deficiency; alitretinoin; alveolar bone; antigen-specific T cells; antimicrobial; base; cytokine; dimer; experimental study; high risk; immune function; improved; improved outcome; in vivo; inflammatory marker; knock-down; lipid metabolism; low income country; macrophage; member; microbicide; mycobacterial; nano-string; prevent; receptor; response; risk minimization; rosiglitazone; transcription factor; tuberculosis immunity; vitamin A receptor

Project Summary Tuberculosis (TB), the leading cause of death due to an infectious disease, is faced by a number of challenges, one of which is our inability to predict disease outcome after exposure. The limited knowledge on risk factors for TB progression and the mechanisms by which these promote susceptibility limits the ability to develop new prevention and treatment approaches. Recently, our collaborators have identified moderate, subclinical vitamin A deficiency as a substantial risk factor for developing active TB, carrying a 10-fold higher risk. The substantial TB risk carried by deficiency in vitamin A highlights the need to understand the mechanisms by which this molecule contributes to protection, particularly in the context of malnutrition among TB-affected communities. Vitamin A functions through nuclear receptors, which are ligand-activated transcription factors. Other nuclear receptors beyond vitamin A receptors have been shown to regulate immune function and contribute to response to M. tuberculosis infection. In particular, PPARγ, a nuclear receptor with obligatory association with vitamin A receptors is enriched in macrophages and influences the immune response during TB. Because we have shown that rosiglitazone, an activator of PPARγ, improves outcome of tuberculosis in guinea pigs, we hypothesize that that availability of vitamin A and PPAR ligands together influence the transcriptional outcome during TB and consequently, the ability to control infection. The goal of this research is to better understand the contribution of nuclear receptor-ligand interaction, and the impact of impaired vitamin A availability on immune response, control of bacterial growth, and TB disease outcome. These will be investigated through Aims using bone marrow- derived macrophage cell models and a guinea pig model of vitamin A deficiency, both developed in our laboratory. We will first determine the contribution of ligand activation of nuclear receptor heterodimers to transcriptional and microbicidal response to infection with M. tuberculosis in bone marrow macrophages. This approach uses a combination of validated knock-down techniques targeting vitamin A (RAR, RXR) and PPARγ receptors, and the vitamin A converting enzyme RALDH, alongside ligand agonists, all-trans retinoic acid (RAR), 9-cis retinoic acid (RXR), and thiazolidenones (PPARγ). This will be followed by the use of our recently developed guinea pig model of dietary vitamin A deficiency to determine the impact of vitamin A and PPARγ signaling on TB immunity. Guinea pigs with sufficient or severely deficient vitamin A status will be treated with or without rosiglitazone, a specific PPARγ agonist, based on our previous assessment of this drug in guinea pigs and immune response and disease outcome measured. Upon completing these experiments, we will have determined the impact of vitamin A and nuclear receptor control over response to infection and consequently, TB disease outcome. These results will guide development of new host-directed therapies to minimize risk and improve outcome of exposure in TB-endemic regions.

项目摘要 结核病(TB)是一种传染病导致的主要死亡原因，面临着许多挑战， 其中之一是我们无法预测暴露后的疾病结果。对疾病风险因素的认识有限 结核病的进展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，我们的合作者已经确定了适度的亚临床维生素 缺乏症是发展活动性结核病的重要风险因素，其风险高出10倍。实质性的 缺乏维生素A带来的结核病风险凸显了了解这一风险的机制的必要性 分子有助于保护，特别是在受结核病影响的社区营养不良的情况下。 维生素A通过核受体发挥作用，核受体是配体激活的转录因子。其他核能 维生素A受体以外的受体已被证明可以调节免疫功能并促进免疫反应 对结核分枝杆菌的感染。尤其是PPARγ，一种与维生素A有强制性联系的核受体 巨噬细胞中的受体丰富，影响结核病期间的免疫反应。因为我们已经证明了 罗格列酮，PPARγ的激活剂，改善了豚鼠结核病的结局，我们假设 维生素A和PPAR配体的可用性共同影响结核病和结核病期间的转录结果 因此，控制感染的能力。这项研究的目标是更好地了解 核受体-配体相互作用以及维生素A供应受损对免疫反应的影响 细菌的生长和结核病的结果。这些将通过使用骨髓的AIMS进行调查- 衍生的巨噬细胞模型和豚鼠维生素A缺乏模型，都是在我们的 实验室。我们将首先确定核受体异二聚体的配体激活对 骨髓巨噬细胞对结核分枝杆菌感染的转录和杀菌反应。这 方法使用了针对维生素A(RAR，RXR)和PPARγ的有效敲除技术的组合 受体和维生素A转换酶RALDH，以及配体激动剂全反式维甲酸(RAR)， 9-顺式维甲酸(RxR)和噻唑烯酮(PPAR)γ。这之后将使用我们最近开发的 饲料中维生素A缺乏豚鼠模型对维生素A和PPARγ信号转导的影响 结核病免疫力。维生素A充足或严重缺乏的豚鼠将接受或不接受治疗 罗格列酮，一种特异性的PPARγ激动剂，基于我们之前对该药物在豚鼠和 测量免疫反应和疾病结局。在完成这些实验后，我们将拥有 确定了维生素A和核受体对感染反应控制的影响，因此， 结核病的转归。这些结果将指导新的宿主导向疗法的开发，以将风险降至最低 改善结核病流行地区的暴露结果。