Host-parasite cross-species regulation by Schistosoma japonicum EV-miRNA sja-miR-2a-3p limits hepatic fibrosis via BCL2 suppression in hepatic stellate cells.

Abstract

Schistosomiasis remains an important zoonotic parasitic disease, and hepatic fibrosis is a major cause of chronic pathology following Schistosoma japonicum infection. In schistosomiasis, hepatic fibrosis is the major cause of severe pathological damage. However, during the long-term co-evolution and coexistence between Schistosoma parasites and their hosts, the parasite can modulate the host hepatic fibrotic process through extracellular vesicle (EV)-mediated cross-species communication. In this study, we identified an EV-derived microRNA from Schistosoma japonicum, sja-miR-2a-3p, that suppresses hepatic pathology in the host. Using transwell co-culture and EV-isolation experiments, we confirmed that the helminth-specific sja-miR-2a-3p could be transferred to hepatic stellate cells (HSCs) via EVs. Bioinformatic and dual-luciferase assays revealed that host BCL2, a major anti-apoptotic gene, is a direct target of sja-miR-2a-3p. In vitro, sja-miR-2a-3p overexpression suppressed HSC proliferation and migration and induced mitochondrial dysfunction, caspase-3/-7/-9 activation, and apoptosis. In vivo, administration of sja-miR-2a-3p agomir to S. japonicum-infected mice significantly downregulated hepatic BCL2 expression, enhanced HSC apoptosis, alleviated granuloma formation, collagen deposition, and inflammation. Collectively, our findings reveal that schistosome EV-delivered sja-miR-2a-3p attenuates liver fibrosis by promoting mitochondrial apoptosis and functionally suppressing HSC activation. This study supports sja-miR-2a-3p as a candidate antifibrotic molecule.