Tearing down the wall: emu-miR-745-3p in Echinococcus multilocularis exosomes attenuates host liver fibrosis to permit invasive lesion development.

Abstract

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis (E. multilocularis), exhibits tumor-like, invasive growth in the liver. Unlike cystic echinococcosis, AE lesions are often bordered by loose fibrosis rather than a dense fibrotic capsule. The mechanism by which the parasite attenuates this host fibrotic response remains unknown. We performed small RNA sequencing of parasite-derived exosomes (EmV-EXOs) and multi-step screening to identify functional miRNAs. The candidate was validated via bioinformatics, dual-luciferase assays, and in vitro studies in hepatic stellate cells (HSCs). An adeno-associated virus (AAV6)-delivered Tough Decoy (TuD) RNA was used for in vivo inhibition in a murine model. emu-miR-745-3p was identified as an exosomal miRNA enriched in EmV-EXOs. It is delivered to HSCs and directly targets the 3' UTR of dipeptidyl peptidase-4 (DPP4), a pro-fibrotic regulator. Downregulation of DPP4 suppressed HSCs activation, reducing expression of α-SMA, COL1A1, and TIMP1. In vivo inhibition of emu-miR-745-3p enhanced perilesional fibrosis, promoted a thicker fibrous capsule, and significantly reduced parasitic lesion burden. E. multilocularis employs exosomal emu-miR-745-3p to attenuate host fibrotic encapsulation, facilitating invasive growth. The emu-miR-745-3p/DPP4 axis is a critical determinant of AE pathology and a potential target for novel anti-fibrotic therapeutics.