The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.
The role of fat on cardiomyopathy outcome in mouse models of chronic Trypanosoma cruzi infection.
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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
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发表时间：
2020
影响因子：
2
通讯作者：
Tanowitz,Herbert
中科院分区：
文献类型：
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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
恰加斯病心肌病的潜在致病机制仍未解决。为了更好地阐明脂肪在心肌病演变中的作用，本研究采用了三种慢性克氏锥虫感染的小鼠模型：（1）aP 2-RIDα/β转基因小鼠（RID小鼠;一种表达功能获得性强效抗炎活性的脂肪组织模型），（2）同种异体移植炎性因子-1敲除小鼠（Aif 1 −/−）和（3）aSwissoutbred小鼠。RID小鼠和非转基因小鼠（野生型，WT）用巴西株的血液锥鞭毛体感染。在感染的急性阶段，RID小鼠的寄生虫血症较低，心脏炎症较低，寄生虫负荷从心肌组织向附睾脂肪的相对分布减少。然而，在感染的慢性阶段，在RID和WT中观察到心肌炎性浸润和寄生虫负荷的相对分布的可比性。Aif 1-/-和Aif 1 +/+小鼠感染Tulahuen株的血流锥鞭毛体，并喂食高脂饮食（HFD）或普通饮食（RD）。有趣的是，Aif 1 +/+HFD感染的小鼠显示出最高的死亡率，在HFD上用Berenice-78株血锥鞭毛体感染的Swissmice比喂食RD的感染小鼠具有更高的TNFα水平和更多的心脏组织炎症。这些不同的小鼠模型暗示脂肪细胞在慢性恰加斯病的发病机制中，并表明HFD可导致寄生虫诱导的慢性心脏损伤的严重程度显著增加。此外，这些数据表明，在慢性恰加斯病的发展中，脂肪细胞TLR 4-、TNFα-和IL-1β介导的促炎通路信号传导和Aif-1基因表达。
The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronicTrypanosoma cruziinfection: (1) aP2-RIDα/β transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1−/−), and (3) aSwissoutbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1−/−and Aif1+/+mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+HFD infected mice showed the highest mortality.Swissmice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1β-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.