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: 10320075
• 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/10320075
• 关键词: AIDS/HIV problem; 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; Homeostasis; Immune system; In Vitro; Individual; Infection; Link; Lung; Mediating; Metabolic; 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.

世界上大约三分之一的人口感染了结核分枝杆菌（Mtb），其中约10%的人 在某些情况下，个体会发展为活动性结核病（TB）。结核病复发的风险在人类中更大 受2型糖尿病（T2 DM）和艾滋病毒影响，而矛盾的是，肥胖可以预防结核病 疾病解释这些合并症如何影响结核病的潜在分子机制 进展大多是未知的。尽管许多研究表明免疫系统不健全， 肺结核再激活发病机制，我们发表的数据链接肺结核发病机制和细菌 脂肪组织（AT）病理生理学负担。本提案的目的是剖析 脂肪细胞/AT在调节肺发病机制中的免疫代谢机制， 脂肪丢失或脂肪生成在肺结核感染发病机制中的意义。我们的中央 一种假设是，脂肪细胞的急性丧失扰乱了肺中的免疫代谢稳态， 在结核分枝杆菌感染期间，通过脂联素（一种抗炎脂肪因子）信号传导扰乱免疫细胞活化。 这一假设得到了我们发表的数据的有力支持，这些数据表明，脂肪细胞的消融 诱导脂联素（一种抗炎脂肪因子）在肺部的表达， 泡沫状巨噬细胞并升高肺中的结核分枝杆菌负荷。此外，我们发现死亡的脂肪细胞 释放表达脂联素的凋亡小体（ApoBD）在肺中积聚， 感染小鼠的肺脂肪形成。将通过追求三个具体目标来检验中心假设： 1)研究AT中脂肪消融和脂肪生成对肺病理学和Mtb负荷的影响， 急性和慢性结核分枝杆菌感染; 2）检查脂肪细胞的增加或减少对结核分枝杆菌感染的调节作用。 急性和慢性感染期间AT和肺中免疫细胞的活化状态;和3） 探讨脂肪细胞通讯机制在调节肺脂联素表达、免疫、 细胞活化和Mtb感染期间的病理学。这项建议在技术上是创新的， 饮食诱导的脂肪形成和脂肪量可消除的鼠TB模型的组合以操纵体脂肪 研究脂肪细胞和脂肪因子在调节肺结核感染严重程度中的作用。一 该申请的显著优势在于所提出的研究设计，其包括独特的动物模型、饮食、 干预，不同的结核分枝杆菌菌株，两种疾病模型和各种体外研究。拟议的研究是 意义重大，因为它将确定脂肪细胞生理学和结核病之间的分子联系， 脂联素信号在肺结核感染发病机制和严重程度中的作用结果会有 一个重要的积极影响，因为拟议的研究将有助于促进确定治疗 结核病复发风险人群早期干预的目标，并将影响临床决策 关于结核病临床管理。