Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy.
Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy.
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DOI：
10.3389/fcimb.2022.904747
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发表时间：
2022
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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查加斯病是一种由克氏锥虫引起的热带人畜共患病。感染后，宿主呈现急性期，通常无症状，其中发生广泛的寄生虫增殖和强烈的先天免疫活性，随后是慢性期，其特征在于低寄生虫血症和特异性免疫的发展。大多数处于慢性期的个体仍然没有症状或器官损伤，这种状态称为不确定的IND形式。然而，20%至40%的人在生命中的任何时候都会出现心脏或胃肠道并发症。心肌细胞在慢性恰加斯心肌病（CCC）的发展中起着重要作用，这是由于转录和代谢改变对寄生虫的生存和复制至关重要。然而，目前还不清楚为什么一些感染者进展到心肌病阶段，而其他人仍然没有症状。在这项工作中，我们使用hiPSCs衍生的心肌细胞（hiPSC-CM）来研究IND和CCC患者的感染，增殖和转录反应模式。我们的数据表明T.在来自两组的PBMC和hiPSC-CM中，cruzi感染和增殖效率没有显著差异。然而，在感染24小时的hiPSC-CM中的RNA-seq分析显示，在来自IND或CCC患者的细胞中对寄生虫的转录应答显著不同。IND的心肌细胞在抗原加工和呈递相关基因以及免疫共刺激分子的表达方面表现出显著差异。此外，这些细胞中胶原蛋白产生基因和细胞外基质成分的下调显著不同。反过来，CCC的心肌细胞表现出mTORC 1通路和未折叠蛋白反应基因的表达增加，两者都与细胞内ROS产生增加有关。这些数据指出了由组间基线遗传差异确定的不同反应模式，这可能对慢性结局（伴或不伴心脏症状）的发展产生影响。
Chagas disease is a tropical zoonosis caused by Trypanosoma cruzi. After infection, the host present an acute phase, usually asymptomatic, in which an extensive parasite proliferation and intense innate immune activity occurs, followed by a chronic phase, characterized by low parasitemia and development of specific immunity. Most individuals in the chronic phase remain without symptoms or organ damage, a state called indeterminate IND form. However, 20 to 40% of individuals develop cardiac or gastrointestinal complications at any time in life. Cardiomyocytes have an important role in the development of Chronic Chagas Cardiomyopathy (CCC) due to transcriptional and metabolic alterations that are crucial for the parasite survival and replication. However, it still not clear why some infected individuals progress to a cardiomyopathy phase, while others remain asymptomatic. In this work, we used hiPSCs-derived cardiomyocytes (hiPSC-CM) to investigate patterns of infection, proliferation and transcriptional response in IND and CCC patients. Our data show that T. cruzi infection and proliferation efficiency do not differ significantly in PBMCs and hiPSC-CM from both groups. However, RNA-seq analysis in hiPSC-CM infected for 24 hours showed a significantly different transcriptional response to the parasite in cells from IND or CCC patients. Cardiomyocytes from IND showed significant differences in the expression of genes related to antigen processing and presentation, as well as, immune co-stimulatory molecules. Furthermore, the downregulation of collagen production genes and extracellular matrix components was significantly different in these cells. Cardiomyocytes from CCC, in turn, showed increased expression of mTORC1 pathway and unfolded protein response genes, both associated to increased intracellular ROS production. These data point to a differential pattern of response, determined by baseline genetic differences between groups, which may have an impact on the development of a chronic outcome with or without the presentation of cardiac symptoms.
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影响因子：
14.8
作者：
通讯作者：
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影响因子：
5.8
作者：
Lara, Leonardo da Silva;Andrade-Lima, Leonardo;Pereira, Lygia Veiga
通讯作者：
Pereira, Lygia Veiga
影响因子：
6
作者：
Cunha-Neto, E;Dzao, VJ;Liew, CC
通讯作者：
Liew, CC
DOI：
10.1590/0074-02760160334
发表时间：
2017-03-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Rassi Jr, Anis;Marin Neto, José Antonio;Rassi, Anis
通讯作者：
Rassi, Anis
影响因子：
7.3
作者：
Didié M;Galla S;Muppala V;Dressel R;Zimmermann WH
通讯作者：
Zimmermann WH