The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction
The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction
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DOI：
10.1371/journal.pntd.0006959
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发表时间：
2019-03-01
影响因子：
3.8
通讯作者：
Brehm, Klaus
中科院分区：
文献类型：
--
作者：
Foerster, Sabine;Koziol, Uriel;Brehm, Klaus
肺泡棘球蚴病（AE）是由绦虫多房棘球绦虫的囊性幼虫引起的一种致死性人畜共患病。感染的特点是宿主肝脏内癌细胞样生长，导致广泛纤维化和器官衰竭。迄今为止，关于寄生虫器官向肝脏趋向性的分子机制以及肝脏细胞因子和激素对寄生虫发育的影响研究甚少。我们发现，多房棘虫幼虫期表达了与人类FGF受体同源的成纤维细胞生长因子（FGF）受体家族的三个成员。利用爪蟾表达系统，我们证明了所有三种棘球蚴FGF受体都对存在于肝脏中的人类酸性和碱性FGF作出反应。在这三种情况下，可以通过添加酪氨酸激酶（TK）抑制剂BIBF 1120来阻止激活，该抑制剂用于治疗人类癌症。在生理浓度下，酸性和碱性FGF显著刺激体外寄生虫干细胞形成囊泡，支持囊泡生长。此外，添加人FGF后，寄生虫的丝裂原激活蛋白激酶信号系统受到刺激。bibf1120的存在显著影响了囊泡和寄生虫干细胞的体外存活。结论/意义我们的数据表明，哺乳动物肝脏中存在的FGF并在纤维化过程中上调，通过作用于进化上保守的寄生虫FGF信号系统，支持AE过程中棘球蚴的建立。这些数据对了解AE的器官趋向性和宿主-寄生虫相互作用的分子机制具有重要意义。此外，我们的数据表明，寄生虫的FGF信号系统是开发抗AE新药的有希望的靶点。
Background Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-failure. The molecular mechanisms of parasite organ tropism towards the liver and influences of liver cytokines and hormones on parasite development are little studied to date.Methodology/Principal findings We show that the E. multilocularis larval stage expresses three members of the fibroblast growth factor (FGF) receptor family with homology to human FGF receptors. Using the Xenopus expression system we demonstrate that all three Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which are present in the liver. In all three cases, activation could be prevented by addition of the tyrosine kinase (TK) inhibitor BIBF 1120, which is used to treat human cancer. At physiological concentrations, acidic and basic FGF significantly stimulated the formation of metacestode vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the parasite's mitogen activated protein kinase signalling system was stimulated upon addition of human FGF. The survival of metacestode vesicles and parasite stem cells were drastically affected in vitro in the presence of BIBF 1120.Conclusions/Significance Our data indicate that mammalian FGF, which is present in the liver and upregulated during fibrosis, supports the establishment of the Echinococcus metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling system. These data are valuable for understanding molecular mechanisms of organ tropism and host-parasite interaction in AE. Furthermore, our data indicate that the parasite's FGF signalling systems are promising targets for the development of novel drugs against AE.