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.

世界上约三分之一的人口感染结核分枝杆菌 (Mtb)，其中约 10% 个体在某些时候会患上活动性结核病 (TB) 结核病在人群中重新激活的风险更大。 受 2 型糖尿病 (T2DM) 和 HIV 影响，而矛盾的是，肥胖可以预防结核病 解释这些合并症如何影响结核病的潜在分子机制。 尽管许多研究表明免疫系统功能低下，但大多是未知的。 肺结核再激活发病机制，我们发表的数据将肺结核发病机制和细菌联系起来 该提案的目的是剖析脂肪组织（AT）病理生理学的负担。 脂肪细胞/AT调节肺部发病机制的免疫代谢机制并检查 脂肪减少或脂肪生成在肺结核感染发病机制中的重要性。 假设是脂肪细胞的急剧丧失会扰乱肺部的免疫代谢稳态， 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激活。 我们发表的数据强烈支持这一假设，该数据表明脂肪细胞的消融 诱导脂联素（一种抗炎脂肪因子）的肺部表达，并增加 泡沫状巨噬细胞会增加肺部的结核分枝杆菌负担。此外，我们还发现死亡的脂肪细胞。 释放表达脂联素的凋亡小体 (ApoBD) 在肺部积聚并可能介导 受感染小鼠的肺脂肪生成将通过追求三个具体目标来检验： 1) 研究AT期间脂肪消融和脂肪生成对肺部病理学和结核分枝杆菌负担的影响 急性和慢性 Mtb 感染；2) 检查脂肪细胞的增加或减少对 Mtb 的调节作用。 急性和慢性感染阶段 AT 和肺部免疫细胞的激活状态； 研究脂肪细胞在调节肺脂联素表达、免疫方面的通讯机制 Mtb 感染期间的细胞激活和病理学该提案在我们使用的技术上是创新的。 结合饮食诱导的脂肪形成和脂肪量可修正的小鼠结核病模型来操纵身体脂肪 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。 该应用程序的显着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 Mtb 菌株、两种疾病模型和各种体外研究。 意义重大，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 脂联素信号在肺结核感染的发病机制和严重程度中的作用。 重要的积极影响，因为拟议的研究将有助于促进治疗方法的确定 对有结核病复发风险的人群进行早期干预的目标并将影响临床决策 关于结核病临床管理。