Immunometabolic regulations of pulmonary TB pathogenesis by adiposetissue

世界上大约三分之一的人口感染了结核分枝杆菌(MTB)，其中10%的人≈ 个人会在某一时刻患上活动性结核病(TB)。结核病重新激活的风险在人身上更大 受2型糖尿病(T2 DM)和艾滋病毒的影响，而矛盾的是，肥胖可以预防结核病 疾病。解释这些并存疾病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，免疫系统的无能与 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与细菌联系起来 脂肪组织负担(AT)病理生理学。这项提案的目的是剖析 脂肪细胞/血管紧张素转换酶调控肺发病免疫代谢机制的研究 脂肪减少或脂肪生成在肺结核发病机制中的意义我们的中央 假说是，脂肪细胞的急性丧失扰乱了肺和肺中的免疫代谢动态平衡 在结核分枝杆菌感染期间，通过脂联素(一种抗炎脂肪因子)信号来扰乱免疫细胞的激活。 这一假说得到了我们公布的数据的有力支持，这些数据表明，消融脂肪细胞 诱导肺组织表达脂联素，一种抗炎脂肪因子，并增加 产生泡沫的巨噬细胞，并增加肺中结核分枝杆菌的负担。此外，我们发现濒临死亡的脂肪细胞 释放表达脂联素的凋亡体(ApoBds)在肺内积聚并可能介导 感染小鼠的肺脂肪生成。核心假设将通过追求三个具体目标来检验： 1)研究脂肪消融和脂肪生成对慢性阻塞性肺疾病患者肺组织病理和MTB负荷的影响。 急性和慢性结核分枝杆菌感染；2)研究脂肪细胞的增减对 急性和慢性感染期间AT和肺中免疫细胞的激活状态；3) 脂肪细胞通讯机制研究(S)调节肺脂联素表达、免疫 结核分枝杆菌感染过程中的细胞激活和病理变化。这项提议在技术上是创新的，我们使用了 饮食诱导的成脂和脂肪质量可修正的小鼠结核病模型相结合来控制体脂 目的：探讨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。一个 这一应用的显著优点是拟议的研究设计，其中包括一种独特的动物模型--饮食 干预，不同的结核分枝杆菌株，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和结核病之间的分子联系，并剖析 脂联素信号在肺结核发病机制及严重程度中的作用结果将会有 一个重要的积极影响，因为拟议的研究将有助于确定治疗 结核病复发高危人群早期干预目标及影响临床决策 关于结核病的临床管理。

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.