Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development.
BACKGROUND
The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood.


RESULTS
Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin.


CONCLUSIONS
Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.
Sarah
S
Hemer
Christian
C
Konrad
Markus
M
Spiliotis
Uriel
U
Koziol
Dominik
D
Schaack
Sabine
S
Förster
Verena
V
Gelmedin
Britta
B
Stadelmann
Thomas
T
Dandekar
Andrew
A
Hemphill
University of Würzburg, Institute of Hygiene and Microbiology, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. kbrehm@hygiene.uni-wuerzburg.de.
Klaus
K
Brehm
D000595:Amino Acid Sequence; D000818:Animals; D048210:Echinococcus multilocularis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D015801:Helminth Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008018:Life Cycle Stages / Q000187:drug effects; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D010271:Parasites / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020798:Two-Hybrid System Techniques
D015801:Helminth Proteins; D007328:Insulin; D009281:Naphthalenes; D063065:Organophosphonates; C519736:hydroxy-2-naphthalenyl-methyl phosphonic acid trisacetoxymethylester; D011972:Receptor, Insulin; D005947:Glucose