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

Sabine Förster,Colette Dissous,Klaus Brehm,Mathieu Vanderstraete,Tina Schäfer,Raphael Duvoisin,Katia Cailliau,Uriel Koziol,Mar Siles-Lucas

doi:10.1371/journal.pntd.0006959

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.

Highlights

The flatworm parasite E. multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most dangerous zoonoses of the Northern hemisphere
By cDNA library screening and mining of the available E. multilocularis genome sequence we identified a total of three Echinococcus genes encoding members of the FGFR family of receptor tyrosine kinases (RTK)
A partial cDNA for a gene encoding a tyrosine kinase (TK) with homology to FGFRs was previously cloned for E. granulosus [28] and by RT-PCR amplification of metacestode cDNA as well as 5’-RACE, the entire cDNA of the E. multilocularis ortholog, designated emfr1 (E. multilocularis fibroblast growth factor receptor 1), was subsequently cloned

Summary

Introduction

The flatworm parasite E. multilocularis (fox-tapeworm) is the causative agent of alveolar echinococcosis (AE), one of the most dangerous zoonoses of the Northern hemisphere. Due to the unrestricted growth of the metacestode, blood vessels and bile ducts of the liver tissue of the intermediate host are obstructed, eventually leading to organ failure [1]. Another hallmark of AE is extensive liver fibrosis which can lead to a complete disappearance of the liver parenchyma, and which most probably involves the activation of hepatic stellate cells during chronic infection [4,5]. 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

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