乙型肝炎病毒颗粒会在感染原代人肝细胞后激活toll样受体2信

StephenW

Hepatology. 2020 Jan 11. doi: 10.1002/hep.31112. [Epub ahead of print]
Hepatitis B virus particles activate toll-like receptor 2 signaling initial upon infection of primary human hepatocytes.
Zhang Z1,2, Trippler M1, Real CI1, Werner M1, Luo X1, Schefczyk S1, Kemper T2, Anastasiou OE1,2, Ladiges Y3, Treckmann J4, Paul A4, Baba HA5, Allweiss L3, Dandri M3, Gerken G1, Wedemeyer H1, Schlaak JF6, Lu M2, Broering R1.
Author information

1
    Dept. of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
2
    Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
3
    Dept. of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4
    Dept. of General-, Visceral- and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
5
    Dept. of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
6
    Evangelisches Klinikum Niederrhein GmbH, Duisburg, Germany.

Abstract

To date conflicting data exist, whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first-contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL1B, IL6 and TNF). UV irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune inducing agent. Purified HBV particles on the whole, that were prepared from HBV DNA-positive and protein rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by TLR2 ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both, HBV particles and Pam3Cys led to phosphorylation of ERK1, JNK and p38 mitogen-activated protein kinases as well as NFκB. Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pre-treatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/SCID/beige mice challenged with HBV in vivo immune induction could only marginally be seen. Conclusions: Primary human hepatocytes are able to sense HBV particles via TLR2 leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.

© 2020 by the American Association for the Study of Liver Diseases.
KEYWORDS:

HBV; PHH; TLR2; innate immunity; stealth virus

PMID:
    31925967
DOI:
    10.1002/hep.31112

StephenW

肝病学。 2020年1月11日。doi：10.1002 / hep.31112。 [Epub提前发布]
乙型肝炎病毒颗粒会在感染原代人肝细胞后激活toll样受体2信号。
Zhang Z1,2，Trippler M1，Real CI1，Werner M1，Luo X1，Schefczyk S1，Kemper T2，Anastasiou OE1,2，Ladiges Y3，Treckmann J4，Paul A4，Baba HA5，Allweiss L3，Dandri M3，Gerken G1，Wedemeyer H1，Schlaak JF6，Lu M2和Broering R1。
作者信息

1个
    德国埃森杜伊斯堡-埃森大学埃森大学医院胃肠病学和肝病学系。
2
    德国埃森杜伊斯堡-埃森大学埃森大学医院病毒研究所。
3
    德国汉堡汉堡埃彭多夫大学医学中心内科中心医学系。
4
    德国埃森杜伊斯堡－埃森大学埃森大学医院普通外科，内脏外科和移植外科。
5
    杜伊斯堡-埃森大学，埃森，埃森大学医院病理学系。
6
    Evangelisches Klinikum Niederrhein GmbH，杜伊斯堡，德国。

抽象

迄今为止，关于乙型肝炎病毒（HBV）是否具有诱导先天免疫应答的能力，存在相互矛盾的数据。在这里，我们调查了体内和体外HBV与原代人肝细胞（PHH）首次接触后的细胞变化。 PHH暴露在HBV颗粒中会导致NFκB的核易位，然后表达和分泌炎性细胞因子（IL1B，IL6和TNF）。紫外线照射病毒颗粒可抑制HBV感染性，但不能抑制PHH中细胞因子的诱导，这表明接种物中含有免疫诱导剂。肝素柱分离后，由HBV DNA阳性和富含蛋白质的级分制备的纯化的HBV总体上仍具有对PHH的免疫诱导能力。 HBV诱导的基因表达谱与TLR2配体Pam3Cys诱导的相似，但与病毒传感器TLR3或TLR7-9诱导的不同。用HBV颗粒和Pam3Cys两者治疗PHH会导致ERK1，JNK和p38丝裂原活化蛋白激酶以及NFκB磷酸化。最后，HBV诱导的基因表达可以被TLR2特异性抗体中和。值得注意的是，用HBV进入抑制剂进行的预处理减弱了TLR2介导的对HBV的应答，提示了受体结合相关的机制。在肝脏人源化的uPA / SCID /米色小鼠体内，仅能勉强看到HBV激发的体内免疫诱导。结论：原代人肝细胞能够通过TLR2感测HBV颗粒，从而在体外激活抗HBV免疫反应。这些发现挑战了先前描述的HBV的隐身特性。

©2020年，美国肝病研究协会。
关键字：

乙肝病毒PHH; TLR2；先天免疫;隐形病毒

PMID：
    31925967
DOI：
    10.1002 / hep.31112