A schistosome miRNA promotes host hepatic fibrosis by targeting transforming growth factor beta receptor III.

ABSTRACT

BACKGROUND & AIMS: MicroRNAs (MiRNAs) derived from parasites, and even from plants, have been detected in body fluids and are known to modulate host genes. In this study, we aimed to investigate if the schistosome miRNAs are involved in the occurrence and progression of hepatic fibrosis during Schistosoma japonicum (S. japonicum) infection. METHODS: The presence of miRNAs from S. japonicum (sja-miRNAs) in hepatic stellate cells (HSCs) was detected by RNA sequencing. sja-miRNAs were screened by transfecting HSCs with sja-miRNA mimics. The role of sja-miR-2162 in hepatic fibrosis was evaluated by either elevating its expression in naïve mice or by inhibiting its activity in infected mice, through administration of recombinant adeno-associated virus serotype 8 vectors expressing sja-miR-2162 or miRNA sponges, respectively. RESULTS: We identified a miRNA of S. japonicum, sja-miR-2162, that was consistently present in the HSCs of infected mice. Transfection of sja-miR-2162 mimics led to activation of HSC cells in vitro, characterized by elevation of collagens and α-SMA. The rAAV8-mediated delivery of sja-miR-2162 to naïve mice induced hepatic fibrosis, while sustained inhibition of sja-miR-2162 in infected mice attenuated hepatic fibrosis. The transforming growth factor beta receptor III (TGFBR3), a negative regulator of TGF-ß signaling, was a direct target of sja-miR-2162 in HSCs. CONCLUSIONS: This study demonstrated that pathogen-derived miRNAs directly promote hepatic fibrogenesis in a cross-species manner, and their efficient and sustained inhibition might present a promising therapeutic intervention for infectious diseases. LAY SUMMARY: A schistosome-specific microRNA, sja-miR-2162, is consistently present in the hepatic stellate cells of mice infected with S. japonicum, where it promotes hepatic fibrosis in the host through cross-species regulation of host fibrosis-related genes. The efficient and sustained inhibition of pathogen-derived micRNAs may represent a novel therapeutic intervention for infectious diseases.