A MicroRNA Derived From Schistosoma japonicum Promotes Schistosomiasis Hepatic Fibrosis by Targeting Host Secreted Frizzled-Related Protein 1.

Yange Wang,Nanhang Lei,Dongmei Zhang,Xiaobin Fan,Xufeng Luo,Xing He,Weiqing Pan,Xiaoxi Wang

doi:10.3389/fcimb.2020.00101

Abstract

Schistosomiasis remains a serious parasitic disease, which is characterized by granulomatous inflammation and hepatic fibrosis. MicroRNAs derived from parasites can regulate host genes and cell phenotype. Here, we showed that a miRNA derived from S. japonicum (Sja-miR-1) exists in the hepatic stellate cells (HSCs) of mice infected with the parasite and up-regulates the expression of collagens and α-SMA by targeting secreted frizzled-related protein 1 (SFRP1). A vector-mediated delivery of Sja-miR-1 into naive mice led to hepatic fibrogenesis in the mice. Accordingly, inhibition of Sja-miR-1 in the infected mice led to reduction of the parasite-induced hepatic fibrosis. The mechanism behind the Sja-miR-1-mediated activation of HSC could be through targeting SFRP1 to regulate the Wnt/β-catenin pathway. These findings reveal that parasite-derived small non-coding RNAs are implicated in cross-species regulation of host pathological process and persistent inhibition of Sja-miR-1 may provide a therapeutic potential for the parasite diseases.

Highlights

At present, schistosomiasis is still a serious parasitic disease, which infects more than 240 million people across 78 countries (Colley et al, 2014)
Quiescent hepatic stellate cells (HSCs) undergo activation to become the major source of myofibroblasts, which highly express α-SMA and collagens (Kisseleva et al, 2012). α-SMA is regarded as a marker of HSCs activation, while accumulated collagens, especially COL1α1 and COL3α1, contribute to excessive extracellular matrix (ECM) deposition (Böttcher and Pinzani, 2017)
To determine whether the schistosome sja-pri-miR-1 can be processed into mature sja-miR-1 in mammal cells, we cloned three perfect sjamiR-1 complementary binding sites into pmirGLO luciferase plasmid to generate a sja-miR-1 sensor plasmid, which could regulate the expression of genes encoding firefly luciferase (Fluc) and renilla luciferase (Rluc) reporters (Figure S1A)

Summary

Introduction

Schistosomiasis is still a serious parasitic disease, which infects more than 240 million people across 78 countries (Colley et al, 2014). Followed by infecting humans or animals, schistosome cercariae migrate to the host portal-mesenteric vein system where the female worm lay a large number of eggs that, at a part, are transported to the liver through portal veins, causing egg granuloma and hepatic fibrosis, eventually form cirrhosis which is the main cause of mortality of schistosomiasis. Schistosomiasis is an immune pathological disease (Pearce and Macdonald, 2002). When the eggs deposit in the tissue, the immune response is quickly polarized to Th2 response marked by elevation of IL-13 and IL-4 (Pearce and Macdonald, 2002; Wilson et al, 2007). The Th2-related cytokines are important mediators for regulation of schistosomiasis hepatic fibrosis and progression of the disease (Wilson et al, 2007).

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Conclusion