Schistosoma mansoni TGF-β Receptor II: Role in Host Ligand-Induced Regulation of a Schistosome Target Gene

Abstract

Members of transforming growth factor-beta (TGF-β) superfamily play pivotal roles in development in multicellular organisms. We report the functional characterization of the Schistosoma mansoni type II receptor (SmTβRII). Mining of the S. mansoni expressed sequence tag (EST) database identified an EST clone that shows homology to the kinase domain of type II receptors from different species. The amplified EST sequence was used as a probe to isolate a cDNA clone spanning the entire coding region of a type II serine/threonine kinase receptor. The interaction of SmTβRII with SmTβRI was elucidated and shown to be dependent on TGF-β ligand binding. Furthermore, in the presence of human TGF-β1, SmTβRII was able to activate SmTβRI, which in turn activated SmSmad2 and promoted its interaction with SmSmad4, proving the transfer of the signal from the receptor complex to the Smad proteins. Gynaecophoral canal protein (GCP), whose expression in male worms is limited to the gynaecophoric canal, was identified as a potential TGF-β target gene in schistosomes. Knocking down the expression of SmTβRII using short interfering RNA molecules (siRNA) resulted in a concomitant reduction in the expression of GCP. These data provide evidence for the direct involvement of SmTβRII in mediating TGF-β–induced activation of the TGF-β target gene, SmGCP, within schistosome parasites. The results also provide additional evidence for a role for the TGF-β signaling pathway in male-induced female reproductive development.

The Lophotrochozoan TGF-β signalling cassette - diversification and conservation in a key signalling pathway

“…This echoes the findings of previous studies in schistosomes (Freitas et al, 2007). It has been suggested that S. mansoni could use host ligands as part of its signalling cassette (Osman et al, 2006), which would explain low diversity of these ligands in this species. The lack of rotifer TGF-b ligands is more unusual, and future sequencing efforts in the Rotifera will reveal whether this loss is real, or an artefact of insufficient sequencing depth.…”

“…These complements do not map exactly onto the canonical cassette, but, as hypothesised in Osman et al, (2006) and earlier in this manuscript, their quantity, when compared to the few ligands encoded in its genome, may suggest that these molecules respond to host, rather than endogenous, signalling cues.…”

Helminth Infection and Type 1 Diabetes

“…These findings are mirrored in the human clinical setting, where studies of HIVpositive patients in regions endemic for S. mansoni revealed that fecal egg counts, but not infection intensity, were negatively correlated with CD4 + T cell counts [23]. Further supporting the coevolution of S. mansoni with the mammalian immune system, evidence exists that adult worms can sense the human regulatory cytokine, transforming growth factor beta (TGF-β), and that stimulation with TGF-β induces expression of genes linked to sexual maturation and malefemale interaction and may modulate embryonic development [24][25][26][27]. S. mansoni has thus evolved not only to detect mediators of host immunity, but also to use these signals in its own program of maturation and reproduction.…”

The influence of host hormones and cytokines onEchinococcus multilocularissignalling and development

“…This trematode expresses several RTKs of the insulin-and the EGF-receptor families (Dissous et al, 2006) as well as surface RSKs of the TGF-β/BMP family which are considerably homologous to those of the host. Two of these systems, the EGF-receptor like RTK SER and the TGF-β receptor signalling complex formed by the type I/type II receptor pair SmTβRI/ SmTβRII, are expressed on the surface of larval or adult schistosomes and interact with corresponding host cytokines, EGF and TGF-β, leading to specific responses in the parasite (Beall & Pearce, 2001;Vicogne et al, 2004;Osman et al, 2006). It is, therefore, to be expected that hormonal cross-communication between evolutionary conserved signalling systems of helminth parasites and their hosts is relatively widespread and forms a common principle of host-helminth interaction, at least in flatworms.…”