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.\n\nMethodology/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 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 parasites 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.\n\nConclusions/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 parasites FGF signalling systems are promising targets for the development of novel drugs against AE.\n\nAuthor summaryTo ensure proper communication between their different cell populations, animals rely on secreted hormones and cytokines that act on receptors of target cells. Most of the respective cytokines, such as FGFs, evolved over 500 million years ago and are present in similar form in all animals, including parasitic worms. The authors of this study show that the metacestode larva of the tapeworm E. multilocularis, which grows like a malignant tumor within the host liver, expresses molecules with homology to FGF receptors from mammals. The authors show that human FGF, which is abundantly present in the liver, stimulates metacestode development and that all parasite FGF receptors are activated by human FGF, despite 500 million years of evolutionary distance between both systems. This indicates that cells of the Echinococcus metacestode can directly communicate with cells of the mammalian host using evolutionarily conserved signaling molecules. This mode of host-pathogen interaction is unique for helminths and does not occur between mammals and single-celled pathogens such as protozoans or bacteria. The authors finally demonstrate that BIBF 1120, a drug used to treat human cancer, targets the Echinococcus FGF receptors and leads to parasite death. This opens new ways for the development of anti-parasitic drugs.