Interferon-Induced Macrophage-Derived Exosomes Mediate Antiviral Activity Against Hepatitis B Virus Through miR-574-5p

Abstract

Background Interferon alpha (IFN-α) has been proven effective in treating chronic hepatitis B (CHB) due to its capability to suppress hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) covalently closed circular DNA (cccDNA). However, the underlying mechanisms are blurred. Methods We investigated the antiviral activities of exosomes from responders and non-responders to pegylated IFN-α (PegIFN-α) as well as the supernatants of IFN-α-treated THP-1 (the human leukemia monocyte cell line) derived macrophages. Then the expression profiles of exosomal microRNAs (miRNAs) were analyzed using miRNA sequencing. The luciferase reporter assay was used to locate the binding position of HBV genomic sequence targeted by the identified miRNA. Results Exosomes from PegIFN-α treated patients particularly responders as well as the supernatants of IFN-α-treated macrophages exhibited anti-HBV activities as manifested by the suppression of HBsAg, hepatitis B e antigen (HBeAg), HBV DNA and cccDNA levels in HBV related cell lines. PegIFN-α treatment upregulated exosomal hsa-miR-193a-5p, hsa-miR-25-5p, and hsa-miR-574-5p that could partially inhibit HBV replication and transcription. Hsa-miR-574-5p reduced pgRNA and polymerase mRNA levels by binding to the 2750-2757 position of HBV genomic sequence. Conclusions Exosomes can transfer IFN-α-related miRNAs from macrophages to HBV-infected hepatocytes, and exhibit antiviral activities against HBV replication and expression.

Exosomes in Hepatitis B Virus Transmission and Related Immune Response

“…These IFN-α-related exosomal miRNAs, including miR-25, miR-193 and miR-574, can suppress HBV replication by degrading HBV DNA. Importantly, no change in three IFN-α-related miRNAs was observed in IFN nonresponders (Wu et al 2020) (Table 2). These results suggest that some exosomal miRNAs may be involved in the induction of abnormal immunity by HBV, while some promote the antiviral effects of IFN-α.…”

“…Therefore, it is presumed that some of the miRNAs that are enriched in exosomes can impair the innate immune response by targeting the proinflammatory cytokines degradation in the context of HBV infection. However, a recent study showed that some exosomal miRNAs are increased both in CHB patients who are IFN responders and in THP-1 macrophages (Wu et al 2020). These IFN-α-related exosomal miRNAs, including miR-25, miR-193 and miR-574, can suppress HBV replication by degrading HBV DNA.…”

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

“…Furthermore, macrophage derived exosomes facilitate antiviral activity during chronic HBV infection through miR-574-5p. Exosomes treated with pegylated interferon-α (PegIFN-α) exhibited anti-HBV activities including the suppression of HBsAg, HBeAg, HBV DNA, and covalently closed circular DNA (cccDNA) levels in HBV cell lines, suggesting exosomes can transport IFN-α related miRNAs from macrophages to HBV-infected hepatocytes [ 139 ]. Treatment with PegIFN-α upregulated exosomal hsa-mir-193a-5p, hsa-miR-25-5p, and hsa-miR-574-5p that partially inhibited HBV replication and transcription.…”

Interferon and Hepatitis B: Current and Future Perspectives

“…Beyond the scope of a single cell, cell-to-cell transmission of viral resistance is also a mechanism for amplifying IFN-ainduced antiviral response. IFN-a can induce the transfer of resistance to HBV from nonpermissive liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes (39)(40)(41). Exosomes from IFN-a-treated LNPCs are rich in molecules with antiviral activity.…”