Abstract
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma worldwide. However, the strategy of HBV to escape from the host immune system remains largely unknown. In this study, we examined extracellular vesicles (EVs) secreted from human hepatocytes infected with HBV. EVs includeing exosomes are nano-size vesicles with proteins, mRNAs, and microRNAs (miRNAs), which can be transmitted to different cells. We found that 104 EV associated miRNAs were increased in hepatocytes more than 2-fold by HBV infection. We then selected those that were potentially implicated in immune regulation. Among them, five HBV-induced miRNAs were found to potentially target multiple sequences in the 3′UTR of IL-21, a cytokine that induces anti-viral immunity. Moreover, expression of a reporter gene with the 3′ UTR of human IL-21 mRNA was suppressed by the five miRNAs individually. Finally, IL-21 expression in cloned human T cells was down-regulated by the five miRNAs. Collectively, this study identified the novel 3′ UTR sequences of human IL-21 mRNA and potential binding sites of HBV-induced EV-miRNAs.
Highlights
Extracellular vesicles (EVs) including exosomes are nano-size membrane vesicles released from many cell types and contain various cellular components, including proteins, mRNAs, and microRNAs[1, 2]
We found that five miRNAs were up-regulated in Hepatitis B virus (HBV)-infected hepatocytes, which potentially target the sequences of the 3′UTR of human IL-21 mRNA and down-regulated IL-21 mRNA expression in human T cells
To investigate EV-miRNAs secreted from human hepatocytes infected with HBV, we utilized PXB chimeric mice, in which liver is highly repopulated with human hepatocytes
Summary
Extracellular vesicles (EVs) including exosomes are nano-size membrane vesicles released from many cell types and contain various cellular components, including proteins, mRNAs, and microRNAs (miRNAs)[1, 2]. EVs released from cells infected with various types of viruses exhibit functions that promote infection and propagation of viruses by suppressing host immunity and modification of their microenvironment[16, 17]. Since HBV is a noncytopathic DNA virus, inflammation in the liver is mediated by host immune responses to the HBV-infected hepatocytes[20, 21]. Recent studies on EV-miRNAs from patients infected with HBV have revealed that the profiles of serum www.nature.com/scientificreports/. We investigated EV-miRNAs secreted from HBV-infected human hepatocytes and found that various cytokines involved in anti-viral immunity could be targeted by EV-miRNAs secreted from HBV-infected hepatocytes. We found that five miRNAs were up-regulated in HBV-infected hepatocytes, which potentially target the sequences of the 3′UTR of human IL-21 mRNA and down-regulated IL-21 mRNA expression in human T cells. As IL-21 is known to be an important cytokine involved in anti-virus immunity[26,27,28], IL-21 could be a favorable target to escape from the host immune system
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