Trypanosoma cruzi and AIDS: Role of the Adipocyte

描述（由申请人提供）：恰加斯病由克氏锥虫原虫引起，是拉丁美洲流行地区急性心肌炎和慢性心肌病的重要病因。近年来，它也被认为是艾滋病毒/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。糖代谢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讨。初步数据表明，克氏锥虫侵入培养的脂肪细胞，并在脂肪组织中侵入并持续存在，上调炎症介质。此外，感染这种寄生虫会严重改变葡萄糖代谢和脂联素水平。小鼠感染这种寄生虫30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了变化。我们计划利用我们开发的一种新的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确切时间参与。在这些小鼠中，我们将使用正糖钳夹程序来表征代谢改变。脂肪细胞衍生因子脂联素广泛参与心脏病的发病机制，并在HIV和急性克氏锥虫感染中减少。利用一种新的脂联素缺失小鼠模型，研究脂联素在克氏锥虫感染小鼠心肌肥厚中的作用。在这两种感染克氏锥虫的小鼠模型中，我们将在感染后15-300天的不同时间点通过免疫印迹分析、组织病理学和透射电镜检查来自身体特定区域的脂肪。采用正糖胰岛素钳，检查急性感染期间观察到的低血糖的潜在原因，特别是肝脏糖代谢的调节。将确定急性和慢性高血糖对恰加斯病慢性期寄生虫再激活的影响。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获得新的见解。预计这些研究将显著有助于更好地了解恰加斯病在代谢失调状态下的发展，如艾滋病毒脂肪营养不良患者，与胰岛素敏感性降低和循环脂联素水平降低有关。

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.