The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction.
Animals
Cell Line
Echinococcus multilocularis
/ genetics
Fibroblast Growth Factors
/ pharmacology
Host-Parasite Interactions
Humans
Indoles
/ pharmacology
Larva
/ drug effects
Mitogen-Activated Protein Kinases
/ genetics
Primary Cell Culture
Protein-Tyrosine Kinases
/ genetics
Receptors, Fibroblast Growth Factor
/ genetics
Recombinant Proteins
/ pharmacology
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
25
10
2018
accepted:
21
12
2018
revised:
20
03
2019
pubmed:
9
3
2019
medline:
26
4
2019
entrez:
9
3
2019
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30849083
doi: 10.1371/journal.pntd.0006959
pii: PNTD-D-18-01667
pmc: PMC6426264
doi:
Substances chimiques
Indoles
0
Receptors, Fibroblast Growth Factor
0
Recombinant Proteins
0
Fibroblast Growth Factors
62031-54-3
Protein-Tyrosine Kinases
EC 2.7.10.1
Mitogen-Activated Protein Kinases
EC 2.7.11.24
nintedanib
G6HRD2P839
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0006959Subventions
Organisme : Wellcome Trust
ID : 107475/Z/15/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
The senior author of this work (KB) is currently member of the Editorial Board of PLoS Neglected Tropical Diseases. Otherwise the authors declare that there are no competing interests.
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