Impact of Diabetes and Hyperlipidemia on Host Defense

糖尿病和高脂血症对宿主防御的影响

• 批准号: 8450158
• 负责人: Hardy Kornfeld
• 金额: $ 39.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450158
• 关键词: 1,2-diacylglycerol; AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Advanced Glycosylation End Products; Aerosols; Africa; Alveolar Macrophages; Antigens; Apolipoprotein E; Apoptotic; Attention; Bacillus (bacterium); Biochemical; Biochemical Pathway; Cell Death; Cells; Cessation of life; China; Cholesterol; Chronic; Clinical Research; Complement; Complication; Complications of Diabetes Mellitus; Data; Dendritic Cells; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diglycerides; Disease; Dyslipidemias; Experimental Diabetes Mellitus; Foundations; Functional disorder; Funding; Future; Germ; Glucose; Glucosephosphate Dehydrogenase; Glyburide; Goals; Host Defense; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; In Vitro; India; Infection; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Invaded; Kidney; Knockout Mice; Knowledge; Leukocytes; Low Density Lipoprotein Receptor; Lung; M cell; Mediating; Metabolic Diseases; Methods; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathology; Pathway interactions; Population; Preclinical Testing; Predisposition; Prevention; Protein Isoforms; Protein Kinase C; Proteins; Public Health; Pyruvaldehyde; Receptor Activation; Recruitment Activity; Relative Risks; Retinal; Risk; Risk Factors; Scientist; Sentinel; Serum; Severities; Signal Transduction; Site; Streptozocin; Structure of lymph node of thorax; Testing; Triglycerides; Tuberculosis; Vaccination; Work; adaptive immunity; antimicrobial; base; cell mediated immune response; chemokine; chemotherapy; clinically relevant; clinically significant; cytokine; design; diabetic; glycation; hypercholesterolemia; immunopathology; improved; in vivo; inhibitor/antagonist; insight; killings; lipid metabolism; macrophage; mouse model; nerve injury; non-diabetic; pathogen; prevent; public health relevance; research study; response; time use; trafficking; type I and type II diabetes; vaccination against tuberculosis

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.

描述（由申请人提供）：我们正在研究糖尿病（DM）患者结核病（TB）易感性增加的基础。糖尿病导致的全球人口归因结核病风险与艾滋病毒/艾滋病相同。糖尿病的免疫缺陷没有艾滋病严重，但是糖尿病在印度和中国更为普遍，并且正在急剧增加，这两个国家的结核病发病率已经很高。在这个项目的前3年多的时间里，我们发现患有慢性高血糖症的小鼠比具有较高细菌负担和更严重肺部病理的对照组更容易感染结核病。患有结核病的糖尿病小鼠具有旺盛的Th1偏倚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表达方面没有明显的空白。一个关键的发现是，在对数型细菌复制期间，糖尿病小鼠对结核分枝杆菌（Mtb）的适应性免疫反应被延迟。糖尿病小鼠在mtb感染的肺泡巨噬细胞（AMF）周围形成髓样细胞聚集体的速度较慢，向胸椎淋巴结（TLN）递送杆菌的速度较慢，而胸椎淋巴结是免疫启动的地方。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的焦点以获取杆菌并将其带到TLN以启动适应性反应。我们计划验证这一假设，并研究其免疫学和生化基础。初步数据表明，在结核病早期，糖尿病小鼠中DC募集信号趋化因子的表达水平低于对照小鼠。我们将研究DC在体内的转运，测试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。大多数患有结核病的人类糖尿病患者患有2型糖尿病（T2D），而到目前为止，我们已经建立了胰岛素缺乏型1型糖尿病（T1D）的模型。因此，我们将在小鼠T2D模型中测试结核敏感性。大多数糖尿病并发症是由慢性高血糖介导的，并且T1D和T2D有共同的特征，因此我们期望在这两种模型中发现更多的相似点而不是差异。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结核病防御。我们现在计划测试是否联合高葡萄糖和高胆固醇或甘油三酯协同削弱结核病防御。或者，迄今为止的研究使用的是患有糖尿病的小鼠，但人类可能在发展为糖尿病之前获得潜伏性结核病感染，从而增加发展为活动性结核病的风险。潜伏期不容易在小鼠中建立模型，但相关数据可以从拟议的研究中获得，这些研究在卡介苗接种和抗菌治疗的临床相关模型中测试DM对Mtb继发性反应的影响。最后，我们将通过检测胰岛素或实验性DM并发症治疗对恢复TB防御的作用，探讨糖尿病TB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危险因素。尽管这一课题具有重要意义，但很少受到基础科学家的关注。我们正在解决关于这一日益具有公共卫生重要性的主题的知识方面的重大差距，同时利用我们的模型调查结核病防御方面的基本问题。