Impact of Diabetes and Hyperlipidemia on Host Defense

描述(申请人提供)：我们正在研究糖尿病(DM)中结核病(TB)易感性增加的基础。糖尿病带来的全球人口结核病风险与艾滋病毒/艾滋病相当。糖尿病的免疫缺陷没有艾滋病严重，但糖尿病更普遍，在结核病发病率已经很高的印度和中国，糖尿病的发病率正在急剧上升。在这个项目的前3年，我们发现慢性高血糖的小鼠比那些细菌负荷更高、肺部病理更差的对照组更容易感染结核病。患有结核病的糖尿病小鼠表现出旺盛的Th1偏向细胞介导的免疫反应，在白细胞募集或对结核病防御至关重要的细胞因子的表达方面没有明显的差距。一个重要的发现是，在对数细菌复制期间，糖尿病小鼠对结核分枝杆菌(Mtb)的适应性免疫反应延迟。糖尿病小鼠在结核杆菌感染的肺泡巨噬细胞(AMF)周围形成髓系细胞集合体的速度很慢，并且将细菌运送到胸腔淋巴结(TLN)的速度也很慢，在胸腔淋巴结(TLN)免疫是启动的。我们的数据表明，DM损害了结核病防御的关键早期步骤，即树突状细胞(DC)被招募到感染AMF的病灶获得杆菌，并将它们带到TLN启动适应性反应。我们计划验证这一假设，并研究其免疫学和生物化学基础。试验数据表明，在结核病早期，糖尿病小鼠体内信号DC募集的趋化因子的表达水平低于对照组小鼠。我们将研究DC在体内的转运，检测AMF在体内和体外的前哨功能，以及DM对AMF激活和细胞死亡的影响。大多数人类糖尿病合并结核病患者患有2型糖尿病(T2D)，而我们到目前为止还建立了胰岛素缺乏型1型糖尿病(T1D)的模型。因此，我们将在T2D小鼠模型上测试结核病的敏感性。大多数糖尿病并发症是由慢性高血糖介导的，并且在T1D和T2D中是相同的，所以我们预计在这些模型中发现更多的相似之处多于不同之处。一些糖尿病并发症会因血脂异常而加重。我们发现，高胆固醇血症独立地损害了结核病的防御。我们现在计划测试高糖和高胆固醇或甘油三酯是否协同作用削弱结核病的防御。或者，到目前为止的研究使用的是NAOVE糖尿病小鼠，但人类可能在患糖尿病之前感染潜伏的结核病，这会增加发展成活动性结核病的风险。潜伏期不容易在小鼠身上模拟，但相关数据可以从拟议的研究中获得，该研究在临床相关的卡介苗接种和抗菌治疗模型中测试DM对结核分枝杆菌次级反应的影响。最后，我们将通过检测胰岛素或实验性糖尿病并发症治疗恢复结核病防御的效果来探讨糖尿病结核病易感性的生化基础。糖尿病是非洲以外结核病最重要的获得性风险因素。尽管这个课题意义重大，但却很少受到基础科学家的关注。我们正在解决对一个日益重要的公共卫生主题的认识上的重大差距，同时使用我们的模型来研究结核病防御中的基本问题。 公共卫生相关性：结核病每年导致200万人死亡，世界上三分之一的人口感染了导致这种疾病的细菌。糖尿病增加了携带结核病细菌的人患结核病的风险，糖尿病患者更有可能患有严重疾病，对治疗的反应更差。该项目的目标是找出糖尿病患者结核病易感性增加的原因，以便设计出更好的预防或治疗这种并发症的方法。

DESCRIPTION (provided by applicant): We are studying the basis for increased tuberculosis (TB) susceptibility in diabetes mellitus (DM). The global population-attributable TB risk conferred by DM equals that of HIV/AIDS. Immune deficiency in DM is less severe than AIDS, but DM is more prevalent and is increasing sharply in India and China, which already have high rates of TB. In the first 3+ years of this project we discovered that mice with chronic hyperglycemia are more susceptible to TB than controls with higher bacillary burden and worse lung pathology. Diabetic mice with TB mount an exuberant Th1 biased cell mediated immune response with no evident gaps in leukocyte recruitment or expression of cytokines critical for TB defense. A key discovery was that the adaptive immune response to Mycobacterium tuberculosis (Mtb) is delayed in diabetic mice during the period of logarithmic bacillary replication. Diabetic mice are slow to develop aggregates of myeloid cells around Mtb-infected alveolar macrophages (AMF) and slow to deliver bacilli to the thoracic lymph nodes (TLN) where immunity is primed. Our data suggest the hypothesis that DM impairs a critical early step in TB defense where dendritic cells (DC) are recruited to foci of infected AMF to acquire bacilli and bring them to the TLN to initiate the adaptive response. We plan to test that hypothesis and to investigate its immunological and biochemical basis. Pilot data indicate that chemokines which signal DC recruitment are expressed in lower levels in diabetic than control mice early in TB. We will study DC trafficking in vivo and test the sentinel function of AMF in vivo and in vitro, as well as the impact of DM on AMF activation and cell death. Most human diabetics with TB have type 2 diabetes (T2D), whereas we have so far modeled insulin-deficient type 1 diabetes (T1D). We will therefore test TB susceptibility in mouse models of T2D. Most diabetic complications are mediated by chronic hyperglycemia and are shared by T1D and T2D, so we anticipate finding more similarities than differences in these models. Some diabetic complications are exacerbated by dyslipidemia. We discovered that hypercholesterolemia independently impairs TB defense. We now plan testing whether combined high glucose and high cholesterol or triglyceride synergistically weaken TB defense. Or studies so far used naove diabetic mice but humans may acquire latent TB infection before developing DM, which then raises the risk of developing active TB disease. Latency is not readily modeled in mice, but relevant data can be derived from proposed studies testing the impact of DM on the secondary response to Mtb in clinically relevant models of BCG vaccination and antimicrobial therapy. Finally, we will investigate the biochemical basis of diabetic TB susceptibility by testing effect of insulin or experimental DM complication therapies to restore TB defense. Diabetes is the most significant acquired risk factor for TB outside of Africa. Despite its significance this subject has received little attention from basic scientists. We are addressing a major gap in knowledge about a topic of growing public health importance and at the same time using our models to investigate fundamental issues in TB defense. PUBLIC HEALTH RELEVANCE: Tuberculosis kills two million people every year and one third of the world's population is infected with the germ that causes this disease. Diabetes increases the risk that people carrying the tuberculosis germ will develop tuberculosis disease and people with diabetes are more likely to have severe disease and a worse response to treatment. The goal of this project is to find the reason increased tuberculosis susceptibility in diabetes so that better methods to prevent or treat this complication can be designed.