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: 8104819
• 负责人: Hardy Kornfeld
• 金额: $ 41.13万
• 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/8104819
• 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; 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. 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.

描述（由申请人提供）：我们正在研究糖尿病（DM）中结核病（TB）易感性增加的基础。糖尿病引起的全球人群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急剧增加。在该项目的前3年多时间里，我们发现慢性高血糖小鼠比对照组更易患结核病，其细菌负荷更高，肺部病理学更差。患有TB的糖尿病小鼠产生了旺盛的Th 1偏向性细胞介导的免疫应答，在白细胞募集或对TB防御至关重要的细胞因子表达方面没有明显的缺口。一个关键的发现是，在对数细菌复制期间，糖尿病小鼠对结核分枝杆菌（Mtb）的适应性免疫应答延迟。糖尿病小鼠在结核分枝杆菌感染的肺泡巨噬细胞（AMF）周围形成髓样细胞聚集体的速度缓慢，并且将杆菌递送到免疫启动的胸淋巴结（TLN）的速度缓慢。我们的数据表明，DM损害结核病防御的一个关键的早期步骤，其中树突状细胞（DC）被招募到受感染的AMF病灶获得杆菌，并将它们带到TLN启动适应性反应的假设。我们计划验证这一假设，并研究其免疫学和生物化学基础。初步数据表明，在TB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。我们将在体内研究DC的运输，并在体内和体外测试AMF的哨兵功能，以及DM对AMF活化和细胞死亡的影响。大多数患有TB的人类糖尿病患者患有2型糖尿病（T2 D），而我们迄今为止已经模拟了胰岛素缺乏型1型糖尿病（T1 D）。因此，我们将在T2 D小鼠模型中测试TB易感性。大多数糖尿病并发症是由慢性高血糖介导的，并且是T1 D和T2 D共有的，因此我们预计在这些模型中发现更多的相似性而不是差异。某些糖尿病并发症会因血脂异常而加重。我们发现，高胆固醇血症独立损害结核病防御。我们现在计划测试高葡萄糖和高胆固醇或甘油三酯是否会协同削弱结核病的防御。或者，迄今为止的研究使用了未患糖尿病的小鼠，但人类可能在患糖尿病之前获得潜伏性结核病感染，这会增加患活动性结核病的风险。潜伏期在小鼠中不易建模，但相关数据可来自于在BCG疫苗接种和抗菌治疗的临床相关模型中测试DM对Mtb继发性应答的影响的拟定研究。最后，我们将通过测试胰岛素或实验性糖尿病并发症治疗恢复结核防御的效果来研究糖尿病结核易感性的生化基础。糖尿病是非洲以外结核病最重要的后天危险因素。尽管它的重要性，这个问题很少受到基础科学家的关注。我们正在解决一个关于公共卫生重要性日益增加的主题的知识方面的重大差距，同时使用我们的模型来调查结核病防御中的基本问题。 公共卫生关系：结核病每年造成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菌的人患结核病的风险，糖尿病患者更有可能患上严重的疾病，对治疗的反应也更差。该项目的目标是找到糖尿病患者结核病易感性增加的原因，以便设计更好的方法来预防或治疗这种并发症。