The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

Abstract

BackgroundAlveolar 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 findingsWe 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/SignificanceOur 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.

Mechanism of Fibrosis Induced by Echinococcus spp.

“…In vitro experiments were performed with the natural metacestodes of E. multilocularis (from rodents). Metacestodes were then continuously passaged in mongolian jirds ( Meriones unguiculatus ) [44].…”

Deciphering the role of miR-71 in Echinococcus multilocularis early development in vitro

“…In particular, the germinative cells were shown to be the only mitotic cell type of Echinococcus which gives rise to all differentiated cells [5,7]. The E. multilocularis primary cell cultivation system [8], which initially contains around 80% germinative cells [5], is routinely used in developmental and immunological studies to mimic, in vitro, the transition of oncosphere-derived stem cells into metacestode vesicles [9][10][11][12]. Furthermore, due to their decisive role in parasite proliferation, the germinative cells are one of the most important cell types for the development of novel chemotherapeutics against echinococcosis [13].…”

In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis

“…More recently, signaling pathways mediated by the insulin receptor, epidermal growth factor receptor (EGFR), and fibroblast growth factor receptor families were characterized in E. multilocularis and were suggested to play important roles in hostparasite interaction and in regulation of the larval development and growth of E. multilocularis. Some human RTK signaling inhibitors were reported to impair E. multilocularis signaling components and inhibited, at least in vitro, the growth of the parasite (12)(13)(14).…”