肝内转录组学揭示慢性乙型肝炎患者对干扰素治疗有反应的

StephenW

肝内转录组学揭示慢性乙型肝炎患者对干扰素治疗有反应的基因特征
李宁 1 2 , 于康康 1 2 , 董敏辉 1 2 , 王金宇 1 2 , 杨飞飞 1 2 , 朱浩翔 1 2 , 余洁 1 2 , 杨靖舒 1 2 , 谢文涛 1 2 , 碧迪沙密特拉 3 , 日成毛 1 2 , 吴飞珍 4 , 郭海涛 3 , 张继明 1 2
隶属关系
隶属关系

    1
    复旦大学华山医院国家传染病医学中心传染病与生物安全研究所上海市传染病与生物安全应急响应重点实验室传染病科，上海，中国。
    2
    医学分子病毒学重点实验室（MOE/MOH），复旦大学上海医学院，上海，中国。
    3
    美国匹兹堡大学微生物学和分子遗传学系 UPMC Hillman 癌症中心癌症病毒学项目。
    4
    复旦大学生物医学研究所表观遗传学重点实验室。

    PMID：35815389 DOI：10.1080/22221751.2022.2100831

抽象的

慢性乙型肝炎病毒 (HBV) 感染仍然是世界范围内的重大公共卫生负担。 α-干扰素 (IFNα) 是目前批准用于慢性乙型肝炎 (CHB) 的两种疗法之一，为了探索 IFNα 治疗反应的机制，我们调查了 21 名 CHB 的基线和 24 周治疗肝内基因表达谱患者通过 mRNA-seq。数据分析表明 PegIFNα 治疗显着诱导抗病毒反应。实现 HBV DNA 丢失和 HBeAg 或 HBsAg 血清学转换的反应者表现出更高的倍数变化和更多的上调干扰素刺激基因 (ISG)。有趣的是，在响应者的基线活检样本中观察到某些 ISG 的表达水平较低。在 HBeAg+ 患者中，无应答者的基线 HBeAg 水平高于应答者。更重要的是，HBeAg- 患者的 HBsAg 消失率高于 HBeAg+ 患者。尽管在 HBeAg- 患者中观察到 ISG 的倍数变化大于 HBeAg+ 患者，但 HBeAg+ 应答者中 ISG 的上调超过 HBeAg 应答者。值得注意的是，PegIFNα 治疗增加了单核细胞和肥大细胞浸润，但减少了应答者和无应答者的 CD8 T 细胞和 M1 巨噬细胞浸润，而 B 细胞浸润仅在应答者中增加。此外，共表达分析确定核糖体蛋白是抗病毒反应的关键参与者。数据还表明，IFNα 可能影响与内质网相关的病毒抗原的产生。总的来说，本研究中的肝内转录组分析丰富了我们对 IFN 介导的 CHB 患者抗病毒作用的理解，并为开发改善 IFNα 治疗的潜在策略提供了新的见解。

关键词：慢性乙型肝炎； HBeAg;干扰素治疗；肝活检；转录组。

StephenW

Intrahepatic transcriptomics reveals gene signatures in chronic hepatitis B patients responded to interferon therapy
Ning Li  1   2 , Kangkang Yu  1   2 , Minhui Dong  1   2 , Jinyu Wang  1   2 , Feifei Yang  1   2 , Haoxiang Zhu  1   2 , Jie Yu  1   2 , Jingshu Yang  1   2 , Wentao Xie  1   2 , Bidisha Mitra  3 , Richeng Mao  1   2 , Feizhen Wu  4 , Haitao Guo  3 , Jiming Zhang  1   2
Affiliations
Affiliations

    1
    Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
    2
    Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China.
    3
    Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, United States.
    4
    Key Laboratory of Epigenetics, Institutes of Biomedical Science, Fudan University, China.

    PMID: 35815389 DOI: 10.1080/22221751.2022.2100831

Abstract

Chronic hepatitis B virus (HBV) infection remains a substantial public health burden worldwide. Alpha-interferon (IFNα) is one of the two currently approved therapies for chronic hepatitis B (CHB), to explore the mechanisms underlying IFNα treatment response, we investigated baseline and 24-week on-treatment intrahepatic gene expression profiles in twenty-one CHB patients by mRNA-seq. The data analyses demonstrated that PegIFNα treatment significantly induced antiviral responses. Responders who achieved HBV DNA loss and HBeAg or HBsAg seroconversion displayed higher fold change and larger number of up-regulated interferon-stimulated genes (ISGs). Interestingly, lower expression levels of certain ISGs were observed in responders in their baseline biopsy samples. In HBeAg+ patients, non-responders had relative higher baseline HBeAg levels than responders. More importantly, HBeAg- patients showed higher HBsAg loss rate than HBeAg+ patients. Although a greater fold change of ISGs was observed in HBeAg- patients than HBeAg+ patients, upregulation of ISGs in HBeAg+ responders exceeded HBeAg- responders. Notably, PegIFNα treatment increased monocyte and mast cell infiltration, but decreased CD8 T cell and M1 macrophage infiltration in both responders and non-responders, while B cell infiltration was increased only in responders. Moreover, co-expression analysis identified ribosomal proteins as critical players in antiviral response. The data also indicate that IFNα may influence the production of viral antigens associated with endoplasmic reticulum. Collectively, The intrahepatic transcriptome analyses in this study enriched our understanding of IFN-mediated antiviral effects in CHB patients and provided novel insights into development of potential strategies to improve IFNα therapy.

Keywords: Chronic hepatitis B; HBeAg; Interferon therapy; Liver biopsy; Transcriptome.