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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要结核病（TB）是一种传染病导致死亡的主要原因，它面临着许多挑战，其中之一是我们无法预测暴露后的疾病结果。结核病进展及其促进易感性的机制限制了开发新药物的能力最近，我们的合作者已经确定了适度的、亚临床的维生素。缺乏是发展活动性结核病的重要危险因素，其风险高出 10 倍。维生素 A 缺乏带来的结核病风险凸显了了解这一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。维生素 A 受体以外的受体已被证明可以调节免疫功能并有助于反应尤其是 PPARγ，一种与维生素 A 必然相关的核受体。受体在巨噬细胞中富集并影响结核病期间的免疫反应，因为我们已经证明了这一点。罗格列酮（PPARγ 的激活剂）可改善豚鼠结核病的结果，我们发现维生素 A 和 PPAR 配体的可用性共同影响 TB 和因此，本研究的目的是更好地了解控制感染的贡献。核受体-配体相互作用，以及维生素 A 可用性受损对免疫反应、控制的影响细菌生长和结核病结果将通过 Aims 使用骨髓进行研究。衍生的巨噬细胞模型和维生素 A 缺乏症的豚鼠模型，均在我们的实验室中开发我们将首先确定核受体异二聚体的配体激活对实验室的贡献。骨髓巨噬细胞对结核分枝杆菌感染的转录和杀菌反应。该方法结合了针对维生素 A（RAR、RXR）和 PPARγ 的经过验证的敲除技术受体、维生素 A 转换酶 RALDH，以及配体激动剂、全反式视黄酸 (RAR)、 9-顺式视黄酸（RXR）和噻唑烷酮（PPARγ）随后将使用我们最近开发的。膳食维生素 A 缺乏症的豚鼠模型，以确定维生素 A 和 PPARγ 信号传导的影响结核病免疫力充足或严重缺乏维生素 A 的豚鼠将接受或不接受治疗。罗格列酮，一种特定的 PPARγ 激动剂，基于我们之前在豚鼠中对该药物的评估，完成这些实验后，我们将测量免疫反应和疾病结果。确定了维生素 A 和核受体控制对感染反应的影响，因此，这些结果将指导新的针对宿主的疗法的开发，以最大限度地降低风险和治疗效果。改善结核病流行地区的暴露结果。