Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.
Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.
复制标题
DOI：
10.1371/journal.pntd.0002923
复制
发表时间：
2014-06
影响因子：
3.8
通讯作者：
Grevelding CG
中科院分区：
文献类型：
--
作者：
Buro C;Beckmann S;Oliveira KC;Dissous C;Cailliau K;Marhöfer RJ;Selzer PM;Verjovski-Almeida S;Grevelding CG
血吸虫寄生虫引起血吸虫病，这是世界上最重要的传染病之一。吡喹酮（Paziquantel，PZQ）是几十年来唯一广泛应用于血吸虫病防治的药物。疫苗的缺乏和对PZQ耐药性的恐惧促使人们寻找替代品。蛋白激酶（PKs）的研究表明它们在染色体的多种生理过程中起着重要作用。在其他两个Abl酪氨酸激酶，Smad 1和Smad 2，被确定在曼氏血吸虫，并显示在性腺和胃真皮中转录。伊马替尼是一种已知的用于人类癌症治疗的T-TK抑制剂（Gleevec/Glivec），可阻断Smad 1的活性。伊马替尼在体外对成虫寄生虫的形态和生理表现出显著的影响，导致寄生虫死亡。在这里，我们展示了支持伊马替尼靶向SmCl 2 1/2的建模数据。生化测定证实SmAbl 2活性也受到伊马替尼的抑制。进行微阵列分析和qRT-PCR实验，以阐明伊马替尼在体外成虫体中影响的转录过程，这表明伊马替尼对蠕虫生理学有广泛影响。表面，肌肉，肠道和性腺相关的过程受到影响，例如gynophoral canal蛋白基因GCP，副肌球蛋白，肌联蛋白，血红蛋白酶和组织蛋白酶的差异转录证明。此外，瓦尔-7和卵形成相关基因如酪氨酸酶1、p14和fs 800样基因的转录水平以及包括核糖体蛋白S6激酶和谷氨酸受体的信号传导基因的转录水平受到影响。最后，对所获得的微阵列数据集和先前分析TGFβR1抑制剂对转录的影响的数据的计算机比较分析为TGFβ和Abl激酶信号传导的关联提供了第一个证据。其中，GCP和卵子形成相关基因被确定为共同靶点。数据证实了伊马替尼对蠕虫生理学的广泛负面影响，证实了PK作为感兴趣的靶标的作用。血吸虫病是一种由寄生虫引起的传染病，影响着全世界数百万人。血吸虫病的致病后果是由虫卵诱发严重的器官炎症引起的。吡喹酮被广泛用于治疗血吸虫病;然而，人们担心抗药性的发展。过去几十年的研究为蛋白激酶在染色体中控制生理过程的重要性提供了强有力的证据。发现了两种β-激酶，它们的活性被伊马替尼阻断，伊马替尼是一种被称为Gleevec/Glivec的人类癌症治疗抑制剂。在体外，伊马替尼治疗导致了显着的影响形态和生理学和死亡的成年histosomes。除了对染色体β-激酶进行建模外，我们还研究了伊马替尼对成年S. mansoni通过进行转录组学，发现了对参与表面、肌肉、肠道和性腺相关过程的基因转录的广泛影响。与先前研究数据的计算机模拟比较分析表明，TGFβ和β 1-激酶信号在溶酶体中存在未知的关联。其中，gynophoral canal蛋白基因GCP被确定为共同靶点。所获得的数据表明，伊马替尼对成人海马体中的生理过程的实质性影响，支持蛋白激酶作为感兴趣的靶点的作用。
Schistosome parasites cause schistosomiasis, one of the most important infectious diseases worldwide. For decades Praziquantel (PZQ) is the only drug widely used for controlling schistosomiasis. The absence of a vaccine and fear of PZQ resistance have motivated the search for alternatives. Studies on protein kinases (PKs) demonstrated their importance for diverse physiological processes in schistosomes. Among others two Abl tyrosine kinases, SmAbl1 and SmAbl2, were identified in Schistosoma mansoni and shown to be transcribed in the gonads and the gastrodermis. SmAbl1 activity was blocked by Imatinib, a known Abl-TK inhibitor used in human cancer therapy (Gleevec/Glivec). Imatinib exhibited dramatic effects on the morphology and physiology of adult schistosomes in vitro causing the death of the parasites. Here we show modeling data supporting the targeting of SmAbl1/2 by Imatinib. A biochemical assay confirmed that SmAbl2 activity is also inhibited by Imatinib. Microarray analyses and qRT-PCR experiments were done to unravel transcriptional processes influenced by Imatinib in adult schistosomes in vitro demonstrating a wide influence on worm physiology. Surface-, muscle-, gut and gonad-associated processes were affected as evidenced by the differential transcription of e.g. the gynecophoral canal protein gene GCP, paramyosin, titin, hemoglobinase, and cathepsins. Furthermore, transcript levels of VAL-7 and egg formation-associated genes such as tyrosinase 1, p14, and fs800-like were affected as well as those of signaling genes including a ribosomal protein S6 kinase and a glutamate receptor. Finally, a comparative in silico analysis of the obtained microarray data sets and previous data analyzing the effect of a TGFβR1 inhibitor on transcription provided first evidence for an association of TGFβ and Abl kinase signaling. Among others GCP and egg formation-associated genes were identified as common targets. The data affirm broad negative effects of Imatinib on worm physiology substantiating the role of PKs as interesting targets. Schistosomiasis is an infectious disease caused by schistosome parasites, affecting millions of people worldwide. The pathogenic consequences of schistosomiasis are caused by the eggs inducing severe organ inflammations. Praziquantel is widely used to treat schistosomiasis; however, there is fear of resistance developing. Research in the last decades has provided strong evidence for the importance of protein kinases controlling physiological processes in schistosomes. Two Abl-kinases were discovered, whose activities are blocked by Imatinib, an inhibitor known as Gleevec/Glivec from human cancer therapy. In vitro, Imatinib treatment led to dramatic effects on morphology and physiology and to the death of adult schistosomes. Besides modeling of the schistosome Abl-kinases we investigated the effect of Imatinib on gene expression in adult S. mansoni by performing transcriptomics and discovered a wide influence on the transcription of genes involved in surface-, muscle-, gut- and gonad-associated processes. Comparative in silico analyses with data from a previous study indicated a yet unknown association of TGFβ and Abl-kinase signaling in schistosomes. Among others the gynecophoral canal protein gene GCP was identified as a common target. The data obtained demonstrate a substantial influence of Imatinib on physiological processes in adult schistosomes supporting the role of protein kinases as interesting targets.
登录
查看更多内容
影响因子：
6.7
作者：
Beckmann S;Buro C;Dissous C;Hirzmann J;Grevelding CG
通讯作者：
Grevelding CG
影响因子：
6.7
作者：
Buro C;Oliveira KC;Lu Z;Leutner S;Beckmann S;Dissous C;Cailliau K;Verjovski-Almeida S;Grevelding CG
通讯作者：
Grevelding CG
影响因子：
4
作者：
Dissous, Colette;Ahier, Arnaud;Khayath, Naji
通讯作者：
Khayath, Naji
影响因子：
1.5
作者：
Aragon, Anthony D.;Imani, Reza A.;Blackburn, Vint R.;Cunningham, Charles
通讯作者：
Cunningham, Charles
影响因子：
2.9
作者：
Ahier, A.;Khayath, N.;Dissous, C.
通讯作者：
Dissous, C.