乙型肝炎病毒如何建立持续性感染

StephenW

How the hepatitis B virus establishes persistent infection                                    

by Public Library of Science                                                                           

                                                                                                                        


  Mode of action of HBeAg-induced expansion of mMDSCs in CHB patients. Credit: Yang F, Yu X, Zhou C, Mao R, Zhu M, Zhu H, et al. (2019)      

New research sheds light on how a hepatitis B viral protein stimulates the expansion of immune cells that impair antiviral responses, according to a study published April 18 in the open-access journal PLOS Pathogens by Haitao Guo of the Indiana University School of Medicine, Bin Wang and Jiming Zhang of Fudan University, and colleagues. The findings potentially explain how the hepatitis B virus (HBV) establishes and maintains chronic infection, and could lead to the development of novel therapeutic strategies.

                                                                                HBV is a blood-borne pathogen that chronically infects approximately 350 million people worldwide, and more than 780,000 patients die annually due to HBV-related liver diseases. Chronic HBV infection is associated with impaired virus-specific T-cell responses. Myeloid-derived suppressor cells (MDSCs) are immune cells known to play a critical role in impairing antiviral T-cell responses. In addition, the hepatitis B e-antigen (HBeAg) - a hepatitis B viral protein—may represent a viral strategy to establish persistent infection, but the mechanism remains largely unknown. In the new study, the researchers examined the mechanisms underlying the expansion of MDSCs and the suppression of T-cell responses in persistent HBV infection.
The researchers analyzed the circulation frequency of MDSCs in 164 patients with chronic HBV infection and 70 healthy donors. They found that the frequency of circulating MDSCs in HBeAg-positive patients is higher than in HBeAg-negative patients. Moreover, HBeAg induced the expansion of MDSCs through the upregulation of a molecule called indoleamine-2, 3-dioxygenase (IDO), which plays a critical role in the suppression of T-cell proliferation. According to the authors, the findings suggest a novel mechanism in which HBeAg-induced MDSC expansion impairs T-cell function through the IDO pathway and favors the establishment of persistent HBV infection. The HBeAg-MDSC-IDO axis may therefore serve as an immunotherapeutic target of chronic hepatitis B.
The authors add, "HBV has may tricks to mess up the host immune system for maintaining a persistent infection, HBeAg is one of the culprits. Breaking the HBeAg-IDO-MDSC nexus may hold promise for developing new HBV therapeutics to treat HBeAg-positive patients."

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                                                                                                                                                                                                                                                                                          More information:                                                                                                Yang F, Yu X, Zhou C, Mao R, Zhu M, Zhu H, et al. (2019) Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection. PLoS Pathog 15(4): e1007690. doi.org/10.1371/journal.ppat.1007690

StephenW

乙型肝炎病毒如何建立持续性感染

由公共科学图书馆
HBeAg诱导的CHB患者mMDSCs扩增的作用方式。图片来源：杨福，余,,周C，毛茹，朱敏，朱鹤，等。 （2019）

4月18日发表在印第安纳大学医学院的海涛郭的开放获取期刊“PLOS Pathogens”中发表的一项研究表明，新研究揭示了乙型肝炎病毒蛋白如何刺激免疫细胞扩散，从而影响抗病毒反应。和复旦大学张继明及其同事。该研究结果可能解释乙型肝炎病毒（HBV）如何建立和维持慢性感染，并可能导致新的治疗策略的发展。

HBV是一种血源性病原体，长期感染全球约3.5亿人，每年有超过780,000名患者因HBV相关肝病而死亡。慢性HBV感染与病毒特异性T细胞反应受损有关。髓源性抑制细胞（MDSCs）是已知在损害抗病毒T细胞应答中起关键作用的免疫细胞。此外，乙型肝炎e抗原（HBeAg） - 乙型肝炎病毒蛋白 - 可能代表了建立持续感染的病毒策略，但其机制仍然很大程度上未知。在这项新研究中，研究人员检查了持续性HBV感染中MDSCs扩增和抑制T细胞反应的机制。

研究人员分析了164名慢性HBV感染患者和70名健康捐献者的MDSCs循环频率。他们发现HBeAg阳性患者循环MDSCs的频率高于HBeAg阴性患者。此外，HBeAg通过上调称为吲哚胺-2,3-双加氧酶（IDO）的分子诱导MDSCs的扩增，该分子在抑制T细胞增殖中起关键作用。这组作者说，这些发现提示了一种新机制，其中HBeAg诱导的MDSC扩增通过IDO途径损害T细胞功能，并有利于建立持续的HBV感染。因此，HBeAg-MDSC-IDO轴可作为慢性乙型肝炎的免疫治疗靶点。

作者补充说，“HBV可能会破​​坏宿主免疫系统以维持持续感染，HBeAg是罪魁祸首之一。打破HBeAg-IDO-MDSC关系可能有望开发治疗HBeAg阳性的新型HBV治疗药物。耐心。”

进一步探索
骨髓来源的抑制细胞可以抑制病毒感染吗？
更多信息：杨福，余,,周C，毛茹，朱敏，朱鹤，等。 （2019）乙型肝炎e抗原诱导单核细胞源性抑制细胞的扩增，从而抑制慢性乙型肝炎病毒感染中的T细胞功能。 PLoS Pathog 15（4）：e1007690。 doi.org/10.1371/journal.ppat.1007690

StephenW

Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection

    Feifei Yang ,
    Xueping Yu ,
    Chenliang Zhou,
    Richeng Mao,
    Mengqi Zhu,
    Haoxiang Zhu,
    Zhenxuan Ma,
    Bidisha Mitra,
    Gan Zhao,
    Yuxian Huang,
    Haitao Guo ,
    Bin Wang ,
    Jiming Zhang


    Published: April 18, 2019
    https://doi.org/10.1371/journal.ppat.1007690

   
Abstract

Chronic hepatitis B virus (HBV) infection is associated with functionally impaired virus-specific T cell responses. Although the myeloid-derived suppressor cells (MDSCs) are known to play a critical role in impairing antiviral T cell responses, viral factors responsible for the expansion of MDSCs in chronic hepatitis B (CHB) remain obscure. In order to elucidate the mechanism of monocytic MDSCs (mMDSCs) expansion and T cell function suppression during persistent HBV infection, we analyzed the circulation frequency of mMDSCs in 164 CHB patients and 70 healthy donors, and found that the proportion of mMDSCs in HBeAg (+) CHB patients was significantly increased compared to that in HBeAg (-) patients, which positively correlated with the level of HBeAg. Furthermore, exposure of peripheral blood mononuclear cells (PBMCs) isolated from healthy donors to HBeAg led to mMDSCs expansion and significant upregulation of IL-1β, IL-6 and indoleamine-2, 3-dioxygenase (IDO), and depletion of the cytokines abrogated HBeAg-induced mMDSCs expansion. Moreover, HBeAg-induced mMDSCs suppressed the autologous T-cell proliferation in vitro, and the purified mMDSCs from HBeAg (+) subjects markedly reduced the proliferation of CD4+ and CD8+ T cells and IFN-γ production, which could be efficiently restored by inhibiting IDO. In summary, HBeAg-induced mMDSCs expansion impairs T cell function through IDO pathway and favors the establishment of a persistent HBV infection, suggesting a mechanism behind the development of HBeAg-induced immune tolerance.
Author summary

HBeAg is not a structural component of HBV and is not essential for viral DNA replication, however, HBeAg positivity is associated with high levels of viremia in patients. HBeAg may represent a viral strategy to establish persistent infection, but the mechanism remains largely ambiguous. Growing evidence suggests that chronic HBV infection may be shaped by MDSCs-mediated T-cell exhaustion. Here, we report that the frequency of circulating mMDSCs in HBeAg (+) patients is higher than HBeAg (-) patients and positively correlates with serum HBeAg levels. The correlation is further demonstrated by in vitro HBeAg stimulation of PBMCs, which induced mMDSCs expansion. Furthermore, HBeAg-induced expansion of mMDSCs is dependent upon cytokine IL-6 and IL-1β, and the indoleamine-2, 3-dioxynase (IDO) plays a critical role in the suppression of T cell proliferation and IFN-γ production by HBeAg-activated mMDSCs. Therefore, our findings demonstrate a novel mechanism responsible for mMDSCs expansion in HBeAg (+) patients, and suggest that the HBeAg-mMDSC-IDO axis may serve as an immunotherapeutic target of chronic hepatitis B.

StephenW

乙型肝炎e抗原诱导单核细胞源性抑制细胞扩增，抑制慢性乙型肝炎病毒感染中的T细胞功能

    杨菲菲，
    薛雪萍
    陈良亮，
    Richeng Mao，
    孟梦琪
    朱浩翔，
    马振轩
    比迪莎米特拉，
    甘昭，
    黄蔚贤，
    郭海涛，
    王斌
    张继明


    发布时间：2019年4月18日
    https://doi.org/10.1371/journal.ppat.1007690

   
抽象

慢性乙型肝炎病毒（HBV）感染与功能受损的病毒特异性T细胞应答相关。尽管已知骨髓衍生的抑制细胞（MDSCs）在损害抗病毒T细胞应答中起关键作用，但是导致慢性乙型肝炎（CHB）中MDSCs扩增的病毒因子仍然模糊不清。为了阐明持续性HBV感染过程中单核细胞MDSCs（mMDSCs）扩增和T细胞功能抑制的机制，我们分析了164名CHB患者和70名健康供者的mMDSCs循环频率，发现HBDSAg中mMDSCs的比例（+ ）与HBeAg（ - ）患者相比，CHB患者显着增加，与HBeAg水平呈正相关。此外，从健康供体分离的外周血单核细胞（PBMCs）暴露于HBeAg导致mMDSCs扩增和IL-1β，IL-6和吲哚胺-2,3-双加氧酶（IDO）的显着上调，以及细胞因子的消耗被废除HBeAg诱导的mMDSCs扩增。此外，HBeAg诱导的mMDSCs在体外抑制自体T细胞增殖，来自HBeAg（+）受试者的纯化的mMDSCs显着降低CD4 +和CD8 + T细胞的增殖和IFN-γ的产生，这可通过抑制IDO而有效恢复。 。总之，HBeAg诱导的mMDSCs扩增通过IDO途径损害T细胞功能，并有利于建立持续的HBV感染，这表明HBeAg诱导的免疫耐受的发展背后的机制。
作者摘要

HBeAg不是HBV的结构成分，对病毒DNA复制不是必需的，然而，HBeAg阳性与患者的高水平病毒血症相关。 HBeAg可能代表了建立持续性感染的病毒策略，但其机制仍然很大程度上不明确。越来越多的证据表明慢性HBV感染可能是由MDSCs介导的T细胞衰竭造成的。在这里，我们报告HBeAg（+）患者中循环mMDSCs的频率高于HBeAg（ - ）患者，并且与血清HBeAg水平正相关。通过体外HBeAg刺激诱导mMDSC扩增的PBMC进一步证实了相关性。此外，HBeAg诱导的mMDSCs扩增依赖于细胞因子IL-6和IL-1β，而吲哚胺-2,3-二氧化酶（IDO）在HBeAg抑制T细胞增殖和IFN-γ产生中起关键作用。 - 活化的mMDSC。因此，我们的研究结果证明了一种新的机制，负责HBeAg（+）患者的mMDSCs扩增，并表明HBeAg-mMDSC-IDO轴可作为慢性乙型肝炎的免疫治疗靶点。

StephenW

https://journals.plos.org/plospa ... ournal.ppat.1007690

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