Work

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

Year: 2025

Type: article

Abstract: 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. IMPORTANCE 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.

Source: Microbiology Spectrum

DOI: 10.1128/spectrum.01318-25