Trypanosoma cruzi and AIDS: Role of the Adipocyte

克氏锥虫和艾滋病：脂肪细胞的作用

• 批准号: 7244049
• 负责人: HERBERT Bernard TANOWITZ
• 金额: $ 24.18万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244049
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Acute Myocarditis; Adipocytes; Adipose tissue; Appendix; Body Regions; Cardiomyopathies; Chagas Disease; Chronic; Chronic Phase; Communicable Diseases; Data; Development; Diabetes Mellitus; Dyslipidemias; Electrons; Encephalitis; Epidemic; Euglycemic Clamping; Fatty acid glycerol esters; Figs - dietary; Glucose Clamp; HIV; Heart Diseases; Heart Hypertrophy; Hepatic; Highly Active Antiretroviral Therapy; Histopathology; Hyperglycemia; Hypoglycemia; Immigrant; Immune; Immunoblot Analysis; Immunosuppression; Individual; Infection; Inflammatory; Insulin; Invaded; Knockout Mice; Laboratories; Latin America; Life; Lipoatrophy; Mediator of activation protein; Metabolic; Modeling; Mus; Myocarditis; Obesity; Opportunistic Infections; Organism; Parasites; Pathogenesis; Patients; Prevalence; Procedures; Proteins; Regulation; Role; Scanning; Staging; Therapeutic immunosuppression; Time; Transmission Electron Microscopy; Trypanosoma cruzi; Waxes; adiponectin; cytokine; day; glucose metabolism; in vivo; insight; insulin sensitivity; mouse model; novel

DESCRIPTION (provided by applicant): Chagas' disease caused by the protozoan parasite Trypanosoma cruzi, is an important cause of acute myocarditis and chronic cardiomyopathy in endemic regions of Latin America. In recent years it has also seen observed as an opportunistic infection in individuals with HIV/AIDS. In view of the increase of obesity, diabetes and AIDS in developing world, the relationship between obesity and infectious diseases has become an important issue. The role of glucose metabolism and the role of the fat cell in the pathogenesis of both acute and chronic Chagas' disease have never been fully explored. Preliminary data indicates that T. cruzi invades cultured fat cells and in addition invades and persists in adipose tissue where it upregulates inflammatory mediators. Moreover, infection with this parasite profoundly alters glucose metabolism and adiponectin levels. Thirty days after infection of mice with this parasite, there are alterations in the expressions of various cytokines and other adipose tissue-specific proteins. We plan to utilize a novel mouse model of inducible lipoatrophy that we have developed to determine the precise temporal involvement of adipocytes during both the acute and the chronic stages of Trypanosoma cruzi infection. In these mice we will characterize the metabolic alterations using the euglycemic clamp procedure. The adipocyte-derived factor adiponectin has been widely implicated in the pathogenesis of heart disease and is reduced both in HIV and acute Trypanosoma cruzi infection. Using a novel model of adiponectin null mice, the role of adiponectin in cardiac hypertrophy will be evaluated in Trypanosoma cruzi infected mice. In both of these mouse models infected with Trypanosoma cruzi we will examine fat from specific regions of the body at various time points from 15-300 days post infection by immunoblot analysis, histopathology and transmission electron microscopy. Employing a euglycemic insulin clamp, the underlying causes for the hypoglycemia observed during acute infection, specifically the regulation of hepatic glucose metabolism, will be examined. The effects of acute and chronic hyperglycemia on the reactivation of parasites in the chronic phase of Chagas' disease will be determined. Finally, we will gain new insights into the cardioprotective role of the adipokine adiponectin during the chronic phase of Trypanosoma cruzi infection. It is expected that these studies will contribute significantly towards a better understanding of Chagas' disease development in dysregulated metabolic states such as HIV lipodystrophic patients, associated with decreased insulin sensitivity and decreased circulating levels of adiponectin.

描述（申请人提供）：恰加斯病由原生动物寄生虫克氏锥虫引起，是拉丁美洲流行地区急性心肌炎和慢性心肌病的重要原因。近年来，它也被视为艾滋病毒/艾滋病患者的机会性感染。鉴于发展中国家肥胖、糖尿病和艾滋病的增加，肥胖与传染病之间的关系已成为一个重要问题。葡萄糖代谢的作用和脂肪细胞在急性和慢性恰加斯病发病机制中的作用尚未得到充分探索。初步数据表明，克氏锥虫侵入培养的脂肪细胞，此外还侵入并持续存在于脂肪组织中，并在其中上调炎症介质。此外，这种寄生虫的感染会极大地改变葡萄糖代谢和脂联素水平。小鼠感染这种寄生虫三十天后，各种细胞因子和其他脂肪组织特异性蛋白的表达发生变化。我们计划利用我们开发的新型诱导性脂肪萎缩小鼠模型来确定克氏锥虫感染急性和慢性阶段脂肪细胞的精确时间参与。在这些小鼠中，我们将使用正常血糖钳夹程序来表征代谢变化。脂肪细胞衍生因子脂联素广泛参与心脏病的发病机制，并且在艾滋病毒和急性克氏锥虫感染中都会减少。使用脂联素无效小鼠的新型模型，将在克氏锥虫感染的小鼠中评估脂联素在心脏肥大中的作用。在这两种感染克氏锥虫的小鼠模型中，我们将通过免疫印迹分析、组织病理学和透射电子显微镜检查感染后 15-300 天的不同时间点身体特定区域的脂肪。使用正常血糖胰岛素钳夹，将检查急性感染期间观察到的低血糖的根本原因，特别是肝脏葡萄糖代谢的调节。将确定急性和慢性高血糖对南美锥虫病慢性期寄生虫重新激活的影响。最后，我们将对脂肪因子脂联素在克氏锥虫感染慢性期的心脏保护作用有新的认识。预计这些研究将有助于更好地了解恰加斯病在代谢失调状态下的发展，例如艾滋病毒脂肪营养不良患者，其与胰岛素敏感性降低和脂联素循环水平降低相关。

项目成果

Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion.

• DOI: 10.1371/journal.pntd.0000953
• 发表时间: 2011-02-01
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Nagajyothi F;Weiss LM;Silver DL;Desruisseaux MS;Scherer PE;Herz J;Tanowitz HB
• 通讯作者: Tanowitz HB

The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.

脂肪对慢性克氏锥虫感染小鼠模型心肌病结局的作用。

• DOI: 10.1007/s00436-020-06645-z
• 发表时间: 2020
• 期刊: Parasitology research
• 影响因子: 2
• 作者: Zaki,Paul;Domingues,ElisaLbc;Amjad,FarhadM;Narde,MaiaraB;Gonçalves,KarolinaR;Viana,MirelleL;dePaula,Heberth;deLima,WandersonG;Huang,Huan;Bahia,MariaT;Sherer,PhilippE;DosSantos,FabianeM;Weiss,LouisM;Tanowitz,Herbert
• 通讯作者: Tanowitz,Herbert