慢性感染过程中 HBV 的 IFNα 亚型特异性易感性

StephenW

慢性感染过程中 HBV 的 IFNα 亚型特异性易感性
谢晓红 1 2 , Zehra Karakoese 3 , Dilhumare Ablikim 1 , Julia Ickler 3 , Jonas Schuhenn 3 , 曾晓青 1 , 冯雪梅 1 , 杨学诚 1 , Ulf Dittmer 3 4 , 杨栋梁 1 4 , Kathrin Sutter 3 4 , 刘佳1 4
隶属关系
隶属关系

    1
    【作者单位】： 华中科技大学同济医学院附属协和医院感染科;
    2
    【作者单位】： 福建医科大学漳州附属医院消化内科;
    3
    德国埃森杜伊斯堡-埃森大学埃森大学医院病毒学研究所。
    4
    华中科技大学感染与免疫国际联合实验室，武汉，中国。

    PMID：36311794 PMCID：PMC9616162 DOI：10.3389/fimmu.2022.1017753

抽象的

慢性乙型肝炎病毒 (HBV) 感染仍然是世界范围内的主要健康问题，并且仍然难以治愈。干扰素（IFN）α治疗是临床治疗慢性乙型肝炎的重要方法。IFNα表现出直接的抗病毒作用以及免疫调节活性，可在部分接受治疗的慢性乙型肝炎患者中诱导持续的抗病毒反应。存在许多具有 76-96% 之间高度序列同一性的 IFNα 亚型，其特征在于多样化、非冗余的生物活性。我们之前的研究表明，临床批准的 IFNα2 并不是所有 IFNα 亚型中抗 HBV 治疗最有效的亚型。迄今为止，人们对早期HBV感染期间的IFNα亚型表达模式和持续HBV感染期间的IFNα亚型特异性易感性及其相关细胞机制知之甚少。在这里，我们通过使用完善的流体动力学注射 (HDI) 小鼠模型确定了急性和慢性 HBV 感染期间 Ifna 亚型 mRNA 的表达，并且我们揭示了一组 Ifna 亚型在 HBV 持续复制小鼠脾脏中的短暂但强烈的表达。到 HDI 控制。具有不同 IFNα 亚型的免疫疗法可控制慢性 HBV 感染。在 AAV-HBV 持续感染鼠模型中全面分析了 IFNα 亚型介导的抗病毒反应和免疫激活，并确定鼠 IFNα2 是抑制 HBV 复制的最有效亚型。对免疫反应的进一步分析揭示了鼠 IFNα2 在持续性 HBV 感染期间对脾脏和肝内 NK 和 T 细胞活化的强免疫调节活性。总之，我们的数据提供了抗病毒和免疫调节效应反应的 IFNα 亚型特异性差异，以及在小鼠持续 HBV 感染期间脾脏中所有 IFNα 亚型的强表达。这些知识将支持开发针对慢性乙型肝炎感染的新型免疫治疗策略。

关键词：干扰素诱导；干扰素α亚型；乙型肝炎病毒;流体动力喷射；持续感染。

版权所有 © 2022 Xie、Karakoese、Ablikim、Ickler、Schuhenn、Zeng、Feng、Yang、Dittmer、Yang、Sutter 和 Liu。

StephenW

IFNα subtype-specific susceptibility of HBV in the course of chronic infection
Xiaohong Xie  1   2 , Zehra Karakoese  3 , Dilhumare Ablikim  1 , Julia Ickler  3 , Jonas Schuhenn  3 , Xiaoqing Zeng  1 , Xuemei Feng  1 , Xuecheng Yang  1 , Ulf Dittmer  3   4 , Dongliang Yang  1   4 , Kathrin Sutter  3   4 , Jia Liu  1   4
Affiliations
Affiliations

    1
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
    2
    Department of Gastroenterology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China.
    3
    Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
    4
    Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China.

    PMID: 36311794 PMCID: PMC9616162 DOI: 10.3389/fimmu.2022.1017753

Abstract

Chronic hepatitis B virus (HBV) infection continues to be a major health problem worldwide and remains hard to be cured. Therapy with interferon (IFN) α is an important method for the clinical treatment of chronic hepatitis B. IFNα exhibits direct antiviral effects as well as immunomodulatory activities, which can induce sustained antiviral responses in part of the treated chronic hepatitis B patients. Numerous IFNα subtypes with high sequence identity between 76-96% exist which are characterized by diverse, non-redundant biological activities. Our previous studies have demonstrated that the clinically approved IFNα2 is not the most effective subtype for the anti-HBV treatment among all IFNα subtypes. So far very little is known about the IFNα subtype expression pattern during early HBV infection and the IFNα subtype-specific susceptibility during persistent HBV infection as well as its related cellular mechanism. Here we determined the Ifna subtype mRNA expression during acute and chronic HBV infection by using the well-established hydrodynamic injection (HDI) mouse model and we revealed a transient but strong expression of a panel of Ifna subtypes in the spleen of HBV persistent replication mice compared to HDI controls. Immunotherapy with distinct IFNα subtypes controlled chronic HBV infection. IFNα subtype-mediated antiviral response and immune activation were comprehensively analyzed in an AAV-HBV persistent infection murine model and murine IFNα2 was identified as the most effective subtype in suppression of HBV replication. Further analysis of the immune response revealed a strong immunomodulatory activity of murine IFNα2 on splenic and intrahepatic NK and T cell activation during persistent HBV infection. Taken together, our data provide IFNα subtype-specific differences in the antiviral and immunomodulatory effector responses and a strong expression of all IFNα subtypes in the spleen during persistent HBV infection in mice. This knowledge will support the development of novel immunotherapeutic strategies for chronic hepatitis B infection.

Keywords: IFN induction; IFNα subtypes; hepatitis B virus; hydrodynamic injection; persistent infection.

Copyright © 2022 Xie, Karakoese, Ablikim, Ickler, Schuhenn, Zeng, Feng, Yang, Dittmer, Yang, Sutter and Liu.

StephenW

https://www.frontiersin.org/arti ... mu.2022.1017753/pdf