Trypanosoma cruzi and AIDS: Role of the Adipocyte

描述(申请人提供)：查加斯病由原生动物寄生虫锥虫克鲁兹引起，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，它也被认为是艾滋病毒/艾滋病患者中的一种机会性感染。鉴于肥胖、糖尿病和艾滋病在发展中国家的增加，肥胖与传染病的关系已成为一个重要的问题。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一直没有得到充分的研究。初步数据表明，克氏毛滴虫入侵培养的脂肪细胞，此外还入侵并持续存在于脂肪组织中，在那里它上调炎症介质。此外，感染这种寄生虫会深刻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变化。我们计划利用我们开发的一种新的可诱导性脂肪萎缩的小鼠模型来确定在克氏锥虫感染的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被广泛认为与心脏病的发病机制有关，在HIV和急性克氏锥虫感染中脂联素都减少。利用脂联素缺失小鼠的新模型，将在克氏锥虫感染的小鼠中评估脂联素在心肌肥大中的作用。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子显微镜检查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潜在原因，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查加斯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获得新的见解。预计这些研究将有助于更好地了解查加斯病在代谢紊乱状态下的发展，例如与胰岛素敏感性下降和循环脂联素水平下降相关的艾滋病毒脂营养不良患者。

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.