Among the diverse groups of infectious agents (e.g. bacteria, fungi, viruses, protozoa), parasitic helminths are in so far unique as they rely on developmental mechanisms which have arisen early in metazoan evolution and are, therefore, also present in their various metazoan hosts. One of the earliest steps in animal evolution was the development of cell-cell communication mechanisms and the basic toolkit of respective systems was already established in the most primitive, sponge-like animals. Hence, hormones and cytokines of the insulin-, the epidermal growth factor (EGF)-, the fibroblast growth factor (FGF)-, or the transforming growth factor-beta/bone morphogenetic protein (TGF-beta/BMP)-families which signal through receptor tyrosine- and receptor serine/threonine kinases (RTKs, RSKs), are used for cell-cell communication in a wide variety of metazoans as different as cnidaria, insects, nematodes and mammals.
The questions we address in this project are: (1) Are evolutionary conserved signalling systems also present in E. multilocularis and other cestodes?; (2) If so, can these systems be stimulated by corresponding host cytokines?; (3) Do host cytokines and hormones influence parasite development in vitro and in vivo?; (4) Could parasite cytokines also influence the cognate signaling systems of the host (e.g. to modulate the immune response)?
As shown in figure 1 (below), we could indeed characterize several evolutionarily conserved signalling systems of the insulin-, the EGF-, the FGF-, and the TGF-beta/BMP-families in E. multilocularis. This included respective surface receptors (tyrosine and serine/threonine kinases; Spiliotis et al., 2003; Konrad et al., 2003; Zavala-Gongora et al., 2006) as well as downstream signalling molecules which form part of the MAP kinase cascade (receptor tyrosine kinase signalling; Spiliotis and Brehm, 2004; Spiliotis et al., 2005; Spiliotis et al., 2006; Gelmedin et al., 2008, 2010) or the Smad transcription factor system (TGF-beta/BMP signalling; Zavala-Gongora et al., 2003; Zavala-Gongora et al., 2008; Epping et al., 2011). Additional components of these signaling pathways were finally revealed by sequencing the E. multilocularis genome (Tsai et al., 2013). For three of the receptor systems we were able to demonstrate biochemical cross-communication with host hormones/cytokines (Konrad et al., 2003; Zavala-Gongora et al., 2006; Spiliotis et al., 2006) and we also showed that a parasite-derived member of the nuclear hormone receptor family can interact with serum components (Förster et al., 2011). These data clearly indicate that hormonal cross-communication via evolutionary conserved signalling systems plays an important role in the host-parasite interplay during alveolar echinococcosis. Interestingly, we recently also demonstrated that parasite-derived cytokines can influence host immune responses. In the excretory/secretory fractions of parasite larvae we detected parasite factors that induce apoptosis and tolerogenic properties in host-derived dendritic cells (Nono et al., 2012) and an ortholog to the human T-cell immunomodulatory protein, EmTIP, which drives IFN-gamma release in CD4+ Tcells (Nono et al., 2013).
Nono, J.K., Lutz, M.B., and Brehm, K. EmTIP, a T-cell immunomodulatory protein secreted by the tapeworm Echinococcus multilocularis is important for early metacestode development.
PLoS Negl. Trop. Dis., in press.
Tsai, I.J. et al. (2013) The genomes of four tapeworm species reveal adaptations to parasitism.
Nature 496: 57-63.
Nono, J.K., Pletinckx, K., Lutz, M., Brehm, K. (2012) Excretory/secretory products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro.
PLoS Negl. Trop. Dis. 6: e1516.
Epping, K., Brehm, K. (2011) Echinococcus multilocularis: molecular characterization of EmSmadE, a novel BR-Smad involved in TGF- and BMP signaling.
Exp. Parasitol. 129: 85-94.
Förster, S., Günthel, D., Kiss, F., Brehm, K. (2011) Molecular characterization of a serum-responsive, DAF-12-like nuclear hormone receptor of the fox-tapeworm Echinococcus multilocularis. J. Cell. Biochem. 112: 1630-1642.
Gelmedin, V., Spiliotis, M. & Brehm, K. (2010) Molecular Characterization of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox-tapeworm Echinococcus multilocularis.
Int. J.Parasitol. 40: 555-567.
Gelmedin, V., Caballero-Gamiz, R. & Brehm, K. (2008) Characterization and inhibition of a p38-like mitogen activated protein kinase (MAPK) from Echinococcus multilocularis: antiparasitic activities of p38 MAPK inhibitors.
Biochem. Pharmacol. 76: 1068-1081.
Zavala-Gongora, R., Derrer, B., Gelmedin, V., Knaus, P. & Brehm, K. (2008) Molecular characterisation of a second structurally unusual AR-Smad without MH1 domain and a Smad4 orthologue from Echinococcus multilocularis. Int. J. Parasitol. 38: 161-176.
Spiliotis, M., Konrad, C., Gelmedin, V., Tappe, D., Brückner, S., Mösch, H.U. & Brehm, K.(2006) Characterisation of EmMPK1, an ERK-like MAP kinase from Echinococcus multilocularis which is activated in response to human epidermal growth factor.
Int. J. Parasitol. 36: 1079-1112.
Zavala-Gongora, R., Kroner, A., Bernthaler, P., Knaus, P. & Brehm, K.* (2006) A member of the transforming growth factor- receptor family of Echinococcus multilocularis is activated by human bone morphogenetic protein 2.
Mol. Biochem. Parasitol. 146: 265-271.
Spiliotis, M., Tappe, D., Brückner, S., Mösch, H.U. & Brehm, K. (2005) Molecular cloning and characterization of Ras- and Raf-homologues from the fox-tapeworm Echinococcus multilocularis.
Mol. Biochem. Parasitol. 193: 225-237.
Spiliotis, M., Kroner, A. & Brehm, K.* (2003) Identification, characterization and expression of the gene encoding the epidermal growth factor receptor orthologue from the fox-tapeworm Echinococcus multilocularis. Gene 323: 57-65
Zavala-Góngora, R., Kroner, A., Wittek, B., Knaus, P. & Brehm, K. (2003) Identification and characterisation of two distinct Smad proteins from the fox-tapeworm Echinococcus multilocularis. Int. J. Parasitol. 33: 1665-1677
Konrad, C., Kroner, A., Spiliotis, M., Zavala-Góngora, R. & Brehm, K. (2003) Identification and molecular characterisation of a gene encoding a member of the insulin receptor family in Echinococcus multilocularis. Int. J. Parasitol. 33: 301-312