A schistosome miRNA promotes host hepatic fibrosis by targeting transforming growth factor beta receptor III
Xing He1, Yange Wang1, Xiaobin Fan1
1Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
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-β 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.
Insights
Schistosome microRNAs (miRNAs) promote liver fibrosis by activating hepatic stellate cells. Inhibiting these parasite-derived miRNAs offers a potential therapeutic strategy for infectious diseases like schistosomiasis.
Area of Science:
- Parasitology
- Molecular Biology
- Hepatology
Background:
- MicroRNAs (miRNAs) from parasites can modulate host genes.
- Schistosoma japonicum (S. japonicum) infection can lead to hepatic fibrosis.
- Investigating the role of schistosome miRNAs in hepatic fibrosis is crucial.
Purpose of the Study:
- To determine if schistosome miRNAs contribute to hepatic fibrosis during S. japonicum infection.
- To identify specific schistosome miRNAs involved in fibrosis.
- To explore therapeutic strategies targeting these miRNAs.
Main Methods:
- RNA sequencing to detect S. japonicum miRNAs (sja-miRNAs) in hepatic stellate cells (HSCs).
- Transfection of HSCs with sja-miRNA mimics to assess their effects.
- In vivo studies using recombinant adeno-associated virus vectors to modulate sja-miR-2162 expression in mice.
Main Results:
- A specific sja-miRNA, sja-miR-2162, was identified in HSCs of infected mice.
- sja-miR-2162 activated HSCs in vitro, increasing collagen and α-SMA.
- In vivo, sja-miR-2162 induced hepatic fibrosis, while its inhibition attenuated fibrosis.
- TGFBR3 was identified as a direct target of sja-miR-2162.
Conclusions:
- Pathogen-derived miRNAs, like sja-miR-2162, directly promote hepatic fibrogenesis across species.
- Targeted inhibition of these miRNAs presents a promising therapeutic approach for infectious diseases.
- Understanding cross-species miRNA regulation is key for developing novel treatments.
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