Role of Toll-like receptor 2 in the immune response against hepadnaviral infecti

StephenW

http://www.journal-of-hepatology.eu/article/S0168-8278%2812%2900354-6/abstract
Role of Toll-like receptor 2 in the immune response against hepadnaviral infection

    Xiaoyong Zhang    ,
    Zhiyong Ma    ,
    Hongyan Liu    ,Institute of Virology, University Hospital of Essen, Essen, Germany
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
    Jia Liu    ,
    Zhongji Meng    ,
    Ruth Broering    ,
    Dongliang Yang    ,
    Joerg F. Schlaak    ,
    Michael Roggendorf    ,
    Mengji Lu, Istitute of Virology, University Hospital of Essen, Essen, Germany
Corresponding author. Address: Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. Tel.: +49 201 7233530; fax: +49 201 7235929.

Received 6 November 2011; received in revised form 11 April 2012; accepted 4 May 2012. published online 21 May 2012.



Background & Aims

The Toll-like receptor 2 (TLR2) has recently been recognized to play an important role in the pathogenesis of chronic hepatitis B virus (HBV) infection. In the present study, we examined the role of TLR2 in hepadnaviral infection in hepatoma cell lines and the woodchuck model.
Methods

The expression of TLR2 and pro-inflammatory cytokines was quantified by real time RT-PCR. TLR2-associated signaling pathways in hepatocytes were examined by Western blot. HBV replication and gene expression were assessed by Southern blot, Northern blot and specific ELISA, respectively.
Results

TLR2 ligands activated NF-κB, PI3K/Akt, and different arms of MAPK signaling pathways and induced the production of pro-inflammatory cytokines in hepatocytes. TLR2-mediated innate immune responses led to reduction of HBV/woodchuck hepatitis virus (WHV) replication and gene expression in HepG2.2.15 cells and primary woodchuck hepatocytes. Furthermore, the antiviral activity of TLR2 ligands was abolished by pretreatment with U0126 and rapamycin, inhibitors of the MAPK/ERK and PI3K/Akt pathways, respectively. In the woodchuck model, relatively low levels of TLR2 expression were found in peripheral blood mononuclear cells (PBMCs) and in liver tissues from chronic WHV carriers. TLR2 expression in PBMCs was inversely correlated with WHV DNA titers in acute WHV infection and in entecavir-treated chronic WHV carriers.
Conclusions

These data suggest that hepatocytes play an active role in TLR2-mediated antiviral responses during hepadnaviral infection. The mutual inhibition of HBV replication and TLR2 signaling represents an important aspect of HBV infection and should be considered in the new therapeutic concept against chronic HBV infection.

StephenW

Toll样受体2对嗜肝病毒感染的免疫反应中的作用

    小勇张，
    致用马，
    红岩刘病毒学研究所，埃森，德国埃森大学医院
传染病，华山医院，上海复旦大学，中国系
    刘佳，
    中吉猛，
    露丝Broering
    栋梁杨，
    约尔格楼Schlaak，
    迈克尔Roggendorf
    孟继良Lunstitute病毒学，埃森，德国埃森大学医院
通讯作者InformationCorresponding作者。地址：病毒学研究所，大学医院的埃森，杜伊斯堡 - 埃森大学，Hufelandstrasse 55，45122埃森，德国。电话：+49 201 7233530，传真：+49 201 7235929。

收到2011年11月11在修订后的形式收到2012年4月，2012年5月4日。 2012年5月21日网上公布。



背景与目的

Toll样受体2（TLR2的）最近已承认在慢性乙型肝炎病毒（HBV）感染的发病机制中发挥了重要作用。在本研究中，我们研究了嗜肝病毒感染在肝癌细胞株和土拨鼠模型的TLR2的作用。
方法

定量实时RT-PCR技术的TLR2和促炎细胞因子的表达。 Western blot检测TLR2的相关信号通路在肝细胞。 HBV复制和基因表达的Southern杂交，Northern杂交和特异性ELISA，分别进行了评估。
结果

TLR2的配体激活PI3K/AKT，NF-κB和MAPK信号通路的不同武器和诱导的促炎性细胞因子在肝细胞的生产。导致减少HBV /土拨鼠肝炎病毒（WHV）复制和HepG2.2.15细胞和初级土拨鼠肝细胞中的基因表达的TLR2的介导的先天免疫反应。此外，被废除的TLR2配体的抗病毒活性的MAPK / ERK和PI3K/Akt信号通路抑制剂U0126和雷帕霉素预处理，分别。在土拨鼠模型，发现的TLR2的表达水平相对较低，在外周血单核细胞（PBMCs）中，并从慢性WHV运营商的肝组织。华纳家庭录影的DNA滴度与华纳家庭录影在急性感染和恩替卡韦治疗慢性WHV携带者PBMCs中的TLR2的表达呈负相关。
结论

这些数据表明，在嗜肝病毒感染的肝细胞发挥积极作用TLR2的介导的抗病毒反应。 HBV复制和TLR2信号的相互抑制乙肝病毒感染的一个重要方面，并应考虑对治疗慢性乙肝病毒感染的新概念。

StephenW

For more information, see Editorial
http://www.journal-of-hepatology.eu/article/S0168-8278%2812%2900445-X/fulltext
Fig. 1

Early interplay between HBV, hepatocytes and their microenvironment. During an acute infection, HBV makes its way to the liver. HBV infects hepatocytes after numerous contacts with other liver cells (step 1.1), such as endothelial and Kupffer cells. In these cells, the virus is exposed to PRRs that can detect and signal its presence even before replication occurs (step 2.1). This detection may very rapidly lead to the local production of IFN as well as proinflammatory cytokines (step 2.1), which activate early antiviral programs (step 3) and recruit innate immune cells (NK, NKT, DC, APC…) to the site of replication in an attempt to mount an efficient immune response including adaptive components. But in the mean time the virus develop strategies to escape this early response and ensure its initial spreading (steps 1.2 and 1.3). If the early and delayed antiviral responses, mediated by hepatocyte (step 1.4bis) and immune cells, fail, then the virus can set further evasion strategies which contribute to the progression toward chronicity (steps 1.5 and 1.6). Among other mechanisms, the virus can block immune responses by down regulating the expression of PRRs and/or inhibiting their downstream signalling (step 1.6). This has been demonstrated for TLR2, a sensor involved in the detection of HBcAg (i.e. virus capsid). This inhibition of expression of PRRs or their signalling pathways could be associated with an arrest of local production of IFN and cytokines (step 2.2), thus preventing the development of adaptive immune responses.

有关详细信息，请参阅编辑:

图1

早期乙肝，肝细胞和微环境之间的相互作用。乙肝病毒急性感染期间，使得其对肝脏的方式。乙肝病毒感染肝细胞后与其他肝细胞（步骤1.1），如内皮细胞和枯否细胞，进行了多次接触。在这些细胞中，病毒暴露PRRS，可以检测并表明它的存在，甚至在复制时（步骤2.1）。这种检测很可能迅速导致本地生产干扰素以及炎性细胞因子（步骤2.1），从而激活早期抗病毒程序（步骤3）和招募先天免疫细胞（NK细胞，NKT细胞，DC，装甲运兵车）网站在试图安装一个有效的免疫反应，包括自适应组件的复制。但在病毒的平均时间制定战略，以摆脱这种早期反应，并确保其初始的扩散（步骤1.2和1.3）。如果早期和延迟的抗病毒反应，肝细胞（步骤1.4bis）和免疫细胞介导的，失败了，那么该病毒可以设置进一步的逃税策略，这有助于向慢性进展（步骤1.5和1.6）。在其他机制，可以阻止病毒通过下调PRRS和/或抑制其下游信号（步骤1.6）表达的免疫反应。这已被证明的TLR2的，HBcAg的检测传感器（即病毒衣壳）。这种表达PRRS或信号通路的抑制作用，可以与本地生产的干扰素和细胞因子（步骤2.2）逮捕，从而防止了适应性免疫反应的发展。