# Functional characterization of TGFβ/BMP receptors in Echinococcus granulosus sensu stricto: implications for parasite survival and therapeutic targeting

## TL;DR

This study explores how TGFβ/BMP receptors in a tapeworm help it survive and suggests these receptors could be targeted for new treatments.

## Contribution

The study identifies TGFβ/BMP receptors in Echinococcus granulosus s.s. as potential therapeutic targets for cystic echinococcosis.

## Key findings

- EgTR1 and EgTR2 receptors are expressed during larval stages, with EgTR2 showing high transcription in activated protoscoleces.
- Pharmacological inhibition of TGFβ/BMP signaling reduced parasite viability in vitro and cyst weight in vivo.
- EgTR2 interacts with human BMP2, indicating a unique parasitic adaptation mechanism.

## Abstract

Cystic echinococcosis (CE), a zoonosis caused by the larval stage of the tapeworm Echinococcus granulosus sensu lato (E. granulosus s.l.), remains a global health burden. Despite the conserved role of the transforming growth factor beta (TGFβ)/Smad signaling in cellular regulation across species, the molecular mechanisms of TGFβ/bone morphogenetic proteins (BMP) receptors in E. granulosus sensu stricto (E. granulosus s.s.) are poorly understood. The TGFβ/BMP receptors of E. granulosus s.s. were cloned and molecularly characterized. The positive binding interaction between receptors and their ligands was identified using the yeast two-hybrid system. To investigate the role of TGFβ/BMP signaling in E. granulosus s.s. development and survival, LDN193189 was employed in both the in vitro co-culture system and subsequent in vivo bioassays to investigate its pharmacological effects. Both receptors, E. granulosus type I receptor (EgTR1) and type II receptor (EgTR2), were characterized in E. granulosus s.s. and expressed during the larval stages, with egtr2 showing peak transcriptional levels in activated protoscoleces (PSCs), 40-fold higher than those in cysts. In situ immunofluorescence analysis demonstrated a predominant localization of EgTR1 and EgTR2 within the tegument, suckers, and hooks of PSCs, as well as in the germinal layer of larval cysts. Yeast two-hybrid analysis revealed that EgTR2 interacted with EgTR1 and HsBMP2, but not with HsTGFβ. LDN193189 treatment significantly suppressed the viability of PSCs. In vivo bioassays in mice demonstrated a notable reduction in the weight of cysts in the LDN193189-treated group compared with the dimethyl sulfoxide-treated group. Our results suggest that EgTR1 and EgTR2 regulate E. granulosus s.s. development, identifying TGFβ/BMP signaling as a therapeutic target for CE.

Cystic echinococcosis (CE), a neglected zoonosis caused by E. granulosus s.l., inflicts severe morbidity and economic losses globally. While transforming growth factor beta/bone morphogenetic proteins (TGFβ/BMP) signaling regulates cellular processes across species, its functional role in E. granulosus s.s. remains unexplored. Here, we elucidate the molecular basis of TGFβ/BMP receptor signaling in E. granulosus s.s., revealing that E. granulosus type I receptor (EgTR1) and type II receptor (EgTR2) orchestrate larval development through species-specific ligand interactions. Our findings demonstrate that EgTR2 interacts with Human BMP2 (HsBMP2), establishing a unique parasitic adaptation mechanism. Pharmacological inhibition using LDN193189 caused the suppression of parasite viability in vitro and reduced cyst weight in vivo, validating these receptors as druggable targets. This study provides the evidence linking TGFβ/BMP receptor dynamics to parasitic survival strategies, while identifying a clinically accessible therapeutic avenue for CE. The discovery bridges a critical gap in parasitic helminth biology and advances precision medicine approaches for combating this neglected tropical disease.