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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

基本信息

批准号：
10237418
负责人：
Jyothi Falguni Nagajyothi
金额：
$ 76.06万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10237418
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 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

项目摘要

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），其中约占10%