Evolutionary and functional relationships of cytokines expressed by the helminth Echinococcus multilocularis and its mammalian host
Final Report Abstract
Alveolar echinococcosis, a lethal zoonosis, is caused by infiltrative, tumor-like growth of the matcestode larva of the fox-tapeworm Echinococcus multilocularis within the human liver. Parasite growth can occur for years to decades and is associated with significant suppression of the host immune response. In the present project, evidence was obtained that parasite larvae secrete soluble factors capable of inducing cell death and tolerance in host cells that regulate the immune response. In particular, it was found that parasite products can lead to the induction of Foxp3+ regulatory T-cells, which are strong immune suppressors. Some of the parasite-derived immunomodulatory factors were characterized at the molecular level and one of these, EmACT, displayed clear structural and functional similarities to activin, a human cytokine involved in the down-regulation of the immune system. This indicates that E. multilocularis utilizes its relative close evolutionary relationship to humans for achieving long-term immunosuppression that facilitates parasite persistence within the host. Due to its immunosuppressive activities, EmACT might be further developed into a molecule for the treatment of unwanted immune responses, e.g. in the case of allergies or autoimmunediseases. The present project also decisively contributed to the characterization of the E. multilocularis genome, yielding a plethora of data concerning additional potential immunomodulatory parasite-factors, clues for a closer understanding of parasite development and host-parasite relationship, and a large number novel targets for anti-parasitic chemotherapy, which still poses a significant problem. Based on genomic data showing that E. multilocularis also expresses systems for sensing host-derived hormones and cytokines, it was further established that insulin, which can be found in high concentrations within the host liver, significantly stimulates parasite growth and development and that the parasite insulin-sensing machinery serves as a fruitful target for the development of novel chemotherapeutics. Overall, the characterization of the Echinococcus genome, which was published in the internationally highly recognized journal Nature, gained great interest by the national and international press, leading to respective articles e.g. in BBC News (Weakness mining for tapeworm drugs; March 14, 2013), Nature World News (Tapeworm genomes mapped, March 14, 2013), The Scientist (Targeting tapeworms, March 19, 2013), Medical Daily (Tapeworm treatment: DNA genome mapping reveals medicine targets; March 13, 2013), N24 Wissen (Wissenschaftler entschlüsseln Erbgut des Bandwurms; March 13, 2013), Die Welt (Bandwurmlarven verhalten sich wie Krebstumore; March 13, 2013), or Focus Online (Neue Krebsmedikamente könnten Bandwürmer bekämpfen, march 13, 2013).
Publications
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(2011) Echinococcus multilocularis: molecular characterization of EmSmadE, a novel BR-Smad involved in TGF-β and BMP signaling. Experimental Parasitology 129: 85-94
Epping, K., Brehm, K.
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(2012) Cestode genomics – progress and prospects for advancing basic and applied aspects of flatworm biology. Parasite Immunology 34: 130-150
Olson, P.D., Zarowiecki, M., Kiss, F., Brehm, K.
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(2012) Excretory/secretory products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Neglected Tropical Diseases 6: e1516
Nono, J.K., Pletinckx, K., Lutz, M., Brehm, K.
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(2013) The genomes of four tapeworm species reveal adaptations to parasitism. Nature 496: 57-63
Tsai, I.J., Zarowiecki, M., Holroyd, N., Garciarrubio, A., Sanchez-Flores, A., Brooks, K.L., Tracey, A., Bobes, R.J., Fragoso, G., Sciutto, E., Aslett, M., Beasley, H., Cai, X., Camicia, F., Clark, R., Cucher, M., De Silva, N., Day, T.A., Deplazes, P., Estrada, K., Fernández, C., Holland, P.W.H., Hou, J., Hu, S., Huckvale, T., Hung, S.S., Kamenetzky, L., Keane, J.A., Kiss, F., Koziol, U., Lambert, O., Liu, K., Luo, X., Luo, Y., Macchiaroli, N., Nichol, S., Paps, J., Parkinson, J., Pouchkina-Stantcheva, N., Riddiford, N., Rosenzvit, M., Salinas, G., Wasmuth, J.D., Zamanian, M., Zheng, Y., The Taenia solium Genome Consortium, Cai, J., Soberón, X., Olson, P.D., Laclette, J.P., Brehm, K., Berriman, M.
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(2014) EmTIP, a T-cell immunomodulatory protein secreted by the tapeworm Echinococcus multilocularis is important for early metacestode development. PLoS Neglected Tropical Diseases 8: e2632
Nono, J.K., Lutz, M.B., and Brehm, K.
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(2014) Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development. BMC Biology 12: 5
Hemer, S., Konrad, C., Spiliotis, Koziol, U., M., Schaack, D., Förster, S., Gelmedin, V., Stadelmann, B., Dandekar, T., Hemphill, A., Brehm, K.
