Transforming growth factor-b signalling regulates protoscolex formation in the Echinococcus multilocularis metacestode

Kaethner, Marc - Epping, Kerstin - Bernthaler, Peter - Rudolf, Kilian - Thomann, Irena - Leitschuh, Nadine - Bergmann, Monika - Spiliotis, Markus - Koziol, Uriel - Brehm, Klaus

Resumen:

The lethal zoonosis alveolar echinococcosis (AE) is caused by tumor-like, infiltrative growth of the metacestode larval stage of the tapeworm Echinococcus multilocularis. We previously showed that the metacestode is composed of posteriorized tissue and that the production of the subsequent larval stage, the protoscolex, depends on re-establishment of anterior identities within the metacestode germinative layer. It is, however, unclear so far how protoscolex differentiation in Echinococcus is regulated. We herein characterized the full complement of E. multilocularis TGFb/BMP receptors, which is composed of one type II and three type I receptor serine/threonine kinases. Functional analyzes showed that all Echinococcus TGFb/BMP receptors are enzymatically active and respond to host derived TGFb/BMP ligands for activating downstream Smad transcription factors. In situ hybridization experiments demonstrated that the Echinococcus TGFb/BMP receptors are mainly expressed by nerve and muscle cells within the germinative layer and in developing brood capsules. Interestingly, the production of brood capsules, which later give rise to protoscoleces, was strongly suppressed in the presence of inhibitors directed against TGFb/BMP receptors, whereas protoscolex differentiation was accelerated in response to host BMP2 and TGFb. Apart from being responsive to host TGFb/BMP ligands, protoscolex production also correlated with the expression of a parasite-derived TGFb-like ligand, EmACT, which is expressed in early brood capsules and which is strongly expressed in anterior domains during protoscolex development. Taken together, these data indicate an important role of TGFb/BMP signalling in Echinococcus anterior pole formation and protoscolex development. Since TGFb is accumulating around metacestode lesions at later stages of the infection, the host immune response could thus serve as a signal by which the parasite senses the time point at which protoscoleces must be produced. Overall, our data shed new light on molecular mechanisms of host-parasite interaction during AE and are relevant for the development of novel treatment strategies.


Detalles Bibliográficos
2023
Echinococcosis
TGFb
BMP
Protoscolex
Brood capsulet
Differentiation
Body axes
Development
Inglés
Universidad de la República
COLIBRI
https://hdl.handle.net/20.500.12008/43232
Acceso abierto
Licencia Creative Commons Atribución (CC - By 4.0)
Resumen:
Sumario:The lethal zoonosis alveolar echinococcosis (AE) is caused by tumor-like, infiltrative growth of the metacestode larval stage of the tapeworm Echinococcus multilocularis. We previously showed that the metacestode is composed of posteriorized tissue and that the production of the subsequent larval stage, the protoscolex, depends on re-establishment of anterior identities within the metacestode germinative layer. It is, however, unclear so far how protoscolex differentiation in Echinococcus is regulated. We herein characterized the full complement of E. multilocularis TGFb/BMP receptors, which is composed of one type II and three type I receptor serine/threonine kinases. Functional analyzes showed that all Echinococcus TGFb/BMP receptors are enzymatically active and respond to host derived TGFb/BMP ligands for activating downstream Smad transcription factors. In situ hybridization experiments demonstrated that the Echinococcus TGFb/BMP receptors are mainly expressed by nerve and muscle cells within the germinative layer and in developing brood capsules. Interestingly, the production of brood capsules, which later give rise to protoscoleces, was strongly suppressed in the presence of inhibitors directed against TGFb/BMP receptors, whereas protoscolex differentiation was accelerated in response to host BMP2 and TGFb. Apart from being responsive to host TGFb/BMP ligands, protoscolex production also correlated with the expression of a parasite-derived TGFb-like ligand, EmACT, which is expressed in early brood capsules and which is strongly expressed in anterior domains during protoscolex development. Taken together, these data indicate an important role of TGFb/BMP signalling in Echinococcus anterior pole formation and protoscolex development. Since TGFb is accumulating around metacestode lesions at later stages of the infection, the host immune response could thus serve as a signal by which the parasite senses the time point at which protoscoleces must be produced. Overall, our data shed new light on molecular mechanisms of host-parasite interaction during AE and are relevant for the development of novel treatment strategies.