具有miR-574的外泌体将干扰素介导的抗HBV活性从巨噬细胞转移

StephenW

Exosomes with miR-574 transfer anti-HBV activity mediated by the interferon from macrophage to HBV-infected hepatocyte
Wenyu Wu  1 , Di Wu  1 , Weiming Yan  1 , Yongli Wang  1 , Jie You  1 , Xiaoyang Wan  1 , Dong Xi  1 , Xiaoping Luo  2 , Meifang Han  1 , Qin Ning  1
Affiliations
Affiliations

    1
    Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
    2
    Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

    PMID: 32663850 DOI: 10.1093/infdis/jiaa399

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.

Keywords: HBV cccDNA; IFN-α; exosome; hsa-miR-574-5p; pgRNA.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

StephenW

具有miR-574的外泌体将干扰素介导的抗HBV活性从巨噬细胞转移到HBV感染的肝细胞中
吴文宇1，地吴1，魏明岩1，王永利1，界游1，小杨湾1，西溪1，小平罗2，梅芳汉1，秦宁1
隶属关系
隶属关系

    1个
    华中科技大学同济医学院附属同济医院感染科和传染病研究所，武汉。
    2
    华中科技大学同济医学院附属同济医院儿科，武汉。

    PMID：32663850 DOI：10.1093 / infdis / jiaa399

抽象

背景：干扰素α（IFN-α）具有抑制乙肝表面抗原（HBsAg）和乙肝病毒（HBV）共价闭合环状DNA（cccDNA）的能力，已被证明可有效治疗慢性乙型肝炎（CHB）。但是，潜在的机制是模糊的。

方法：我们研究了应答者和非应答者的外来体对聚乙二醇化IFN-α（PegIFN-α）以及IFN-α处理的THP-1（人白血病单核细胞系）衍生的巨噬细胞的上清液的抗病毒活性。然后使用miRNA测序分析外体microRNA（miRNA）的表达谱。萤光素酶报告基因测定法用于定位已鉴定的miRNA靶向的HBV基因组序列的结合位置。

结果：经过PegIFN-α治疗的患者的外泌体，特别是应答者，以及经IFN-α治疗的巨噬细胞的上清液均表现出抗HBV活性，这通过抑制HBsAg，乙型肝炎e抗原（HBeAg），HBV DNA和cccDNA水平来体现。 HBV相关细胞系。 PegIFN-α治疗上调了外泌体hsa-miR-193a-5p，hsa-miR-25-5p和hsa-miR-574-5p，可部分抑制HBV复制和转录。 Hsa-miR-574-5p通过结合HBV基因组序列的2750-2757位置降低了pgRNA和聚合酶mRNA的水平。

结论：外来体可将巨噬细胞中的IFN-α相关miRNA转移至感染HBV的肝细胞，并具有抗HBV复制和表达的抗病毒活性。

关键字：HBV cccDNA； IFN-α；外泌体hsa-miR-574-5p; pgRNA。

©2020作者。牛津大学出版社，美国传染病学会出版。版权所有。有关权限，请发送电子邮件至：[email protected]。