Immunometabolic regulations of pulmonary TB pathogenesis by adiposetissue

脂肪组织对肺结核发病机制的免疫代谢调节

• 批准号: 10539249
• 负责人: Jyothi Falguni Nagajyothi
• 金额: $ 76.42万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539249
• 关键词: Ablation; Acute; Adipocytes; Adipose tissue; Affect; Animal Model; Anti-Inflammatory Agents; Apoptotic; Body fat; Cells; Chronic; Clinical; Clinical Management; Communication; Data; Diet; Dietary Intervention; Disease; Disease Progression; Disease model; Early Intervention; Fatty acid glycerol esters; Foamy Macrophage; Functional disorder; HIV; HIV/AIDS; Homeostasis; Immune system; In Vitro; Individual; Infection; Link; Lung; Mediating; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathology; Persons; Physiology; Population; Populations at Risk; Publishing; Pulmonary Pathology; Pulmonary Tuberculosis; Regulation; Research; Research Design; Risk; Risk Factors; Role; Severities; Signal Transduction; Testing; Tuberculosis; adipokines; adiponectin; comorbidity; immune activation; immunological status; innovation; lipid biosynthesis; therapeutic target

About one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and ≈10% of these individuals will at some point develop active tuberculosis (TB). The risk of TB reactivation is greater in people affected by type 2 diabetes mellitus (T2DM) and HIV, whereas, paradoxically, obesity protects against TB disease. The underlying molecular mechanisms that explain how these co-morbidities impact TB disease progression are mostly unknown. Although many studies have implicated incompetent immune systems to pulmonary TB reactivation pathogenesis, our published data links pulmonary TB pathogenesis and bacterial burden to adipose tissue (AT) pathophysiology. The objective of this proposal is to dissect the role of adipocytes/AT in regulating immuno-metabolic mechanisms underlying pulmonary pathogenesis and examine the significance of fat loss or adipogenesis in the pathogenesis of pulmonary TB infection. Our central hypothesis is that an acute loss of adipocytes perturbs immuno-metabolic homeostasis in the lungs and upsets immune-cell activation via adiponectin (an anti-inflammatory adipokine) signaling during Mtb infection. This hypothesis is strongly supported by our published data which demonstrates that ablation of fat cells induces pulmonary expression of adiponectin, an anti-inflammatory adipokine, and increases the levels of foamy macrophages and elevates Mtb burden in the lungs. In addition we showed that dying adipocytes release apoptotic bodies (ApoBDs) that express adiponectin accumulate in the lungs and may mediate pulmonary adipogenesis in infected mice. The central hypothesis will be tested by pursuing three specific aims: 1) To study the impact of fat ablation and adipogenesis in AT on pulmonary pathology and Mtb burden during acute and chronic Mtb infections; 2) To examine the regulatory effect of gain or loss of fat cells on the activation status of immune cells in AT and lung during acute and chronic stages of infection; and 3) To investigate adipocytes communication mechanism(s) in regulating pulmonary adiponectin expression, immune cells activation, and pathology during Mtb infection. This proposal is technically innovative in our use of a combination of diet-induced adipogenic and fat-mass amendable murine TB models to manipulate body fat mass to investigate the role of adipocytes and adipokines in regulating pulmonary TB infection severity. A significant strength of this application is the proposed study design which includes a unique animal model, diet intervention, different Mtb strains, two disease models and various in vitro studies. The proposed research is significant, because it will identify the molecular links between adipocyte physiology and TB and dissect the role of adiponectin signaling in the pathogenesis and severity of pulmonary TB infection. The results will have an important positive impact because the proposed studies will help facilitate the identification of therapeutic targets for early intervention in populations at risk for TB reactivation and will impact clinical decisions regarding TB clinical management.

大约三分之一的世界人口感染了结核分枝杆菌（MTB），其中约有10％ 个体在某个时候会发展活跃的结核病（TB）。人体重新激活的风险更大 受2型糖尿病（T2DM）和HIV影响 疾病。解释这些合并症如何影响结核病疾病的基本分子机制 进展主要是未知的。尽管许多研究已经实施了无能的免疫系统 肺结核重新激活发病机理，我们已发表的数据连接肺结核发病机理和细菌 负担脂肪组织（AT）病理生理学。该提议的目的是剖析 脂肪细胞/AT在调节性免疫代谢机制中，肺发病机理并检查 脂肪流失或成脂的重要性在肺结核感染的发病机理中。我们的中心 假设是脂肪细胞的急性丧失肺部免疫代谢稳态和 MTB感染期间通过脂联素（一种抗炎脂肪因子）信号传导的免疫电池激活。 我们已发布的数据强烈支持了这一假设，该数据表明脂肪细胞的消融 诱导脂联素的肺表达，一种抗炎脂肪因子，并增加 泡沫巨噬细胞并提高了肺部的MTB燃烧。此外，我们表明垂死的脂肪细胞 释放凋亡体（APOBD），在肺中表达脂联素丙烯酸，可能介导 感染小鼠的肺脂肪形成。中心假设将通过追求三个具体目标来检验： 1）研究脂肪消融和成脂的影响在AT上对肺病理学和MTB Burnen的影响 急性和慢性MTB感染； 2）检查脂肪细胞获得或损失对脂肪细胞对 急性和慢性感染阶段中AT和肺中免疫细胞的激活状态；和3）到 研究脂肪细胞通信机制在控制肺脂联素表达，免疫时 细胞激活和MTB感染期间的病理。在我们使用一个方面，该建议在技术上是创新的 饮食引起的成脂和脂肪质量修正的鼠结核模型的组合，以操纵体内脂肪 质量研究脂肪细胞和脂肪因子在控制肺结核感染严重程度中的作用。一个 该应用的重要优势是拟议的研究设计，其中包括独特的动物模型，饮食 干预，不同的MTB菌株，两个疾病模型和各种体外研究。拟议的研究是 重要，因为它将确定脂肪细胞生理学与结核病之间的分子联系并剖析 脂联素信号传导在肺结核感染的发病机理和严重程度中的作用。结果将有 重要的积极影响，因为拟议的研究将有助于促进治疗的识别 提早干预有TB重新激活风险的人群的目标，并将影响临床决策 有关结核病临床管理。