Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy
Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-α-2a antiviral therapy
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DOI：
10.1016/j.clinre.2016.12.006
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发表时间：
2017-09-01
影响因子：
2.7
通讯作者：
Zhang, Xiaoyong
中科院分区：
文献类型：
--
作者：
Deng, Guangying;Ge, Jun;Zhang, Xiaoyong
背景与目的：Toll样受体8（TLR8）在控制慢性病毒感染中发挥着重要作用。然而，人们对 TLR8 在慢性乙型肝炎病毒 (HBV) 感染中的作用知之甚少。在本研究中，我们旨在探讨慢性乙型肝炎（CHB）患者外周血单核细胞（PBMC）中TLR8的表达和功能及其在peg-IFN-α-2a治疗期间的变化。方法：我们使用从CHB患者获得的新鲜PBMC进行比较，通过实时RT-PCR和流式细胞术分析来评估TLR8表达和体外抗病毒功能。 到健康的控制。我们还采用临床队列来研究 peg-IFN-α 2a 治疗对 TLR8 表达的反应。结果：TLR8 主要在单核细胞中表达，用其配体模拟可导致高水平的 IFN-γ 和 TNF-α 产生。与健康对照相比，从 CHB 患者获得的 PBMC 显示出 TLR8 表达水平以及 IFN-γ、TNF-α 和 IL-12 诱导水平降低。将 HepG2.2.15 细胞暴露于 ssRNA40 刺激的 PBMC 条件培养基中，会强烈降低 HBV DNA、HBsAg 和 HBeAg 的水平，而添加 IFN-γ 或 TNF-α 中和抗体可能会阻断抗病毒作用。 NK 细胞和 T 细胞是 ssRNA40 刺激后主要产生 IFN-γ 的淋巴细胞，而单核细胞是 TNF-α 的主要来源。时间动态分析表明，从 peg-IFN-α-2a 治疗第 12 周开始，获得完全缓解的患者的 TLR8 mRNA 水平显着高于未获得完全缓解的患者。 结论：慢性 HBV 感染损害了 PBMC 中的 TLR8 表达和功能。治疗第 12 周后较高的 TLR8 表达可能预测对 peg-IFN-α-2a 治疗的完全缓解。 (C) 2017 Elsevier Masson SAS。版权所有。
BACKGROUND AND AIM: Toll-like receptor 8 (TLR8) plays an important role in controlling chronic viral infections. However, the role of TLR8 in chronic hepatitis B virus (HBV) infection is poorly understood. In this study, we aimed to investigate the expression and function of TLR8 in peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B (CHB) patients and its alteration during peg-IFN-alpha-2a therapy.METHODS: We evaluated TLR8 expression and antiviral function in vitro by real-time RT-PCR and flow cytometry analysis using fresh PBMCs obtained from CHB patients compared to healthy controls. We also employed clinical cohorts to investigate TLR8 expression in response to peg-IFN-alpha 2a therapy.RESULTS: TLR8 was mainly expressed in monocytes, and simulation with its ligand resulted in high levels of IFN-gamma and TNF-alpha production. Compared with healthy controls, PBMCs obtained from CHB patients displayed reduced levels of TLR8 expression and IFN-gamma, TNF-alpha and IL-12 induction. The exposure of HepG2.2.15 cells to conditioned medium from PBMCs stimulated by ssRNA40 strongly reduced the levels of HBV DNA, HBsAg and HBeAg, whereas the addition of IFN-gamma or TNF-alpha neutralizing antibodies could block the antiviral effect. NK cells and T cells were the principal IFN-gamma-producing lymphocytes after ssRNA40 stimulation, whereas monocytes were the primary source of TNF-alpha. Analysis of the temporal dynamics showed that patients who achieved a complete response sustained a significant higher level of TLR8 mRNA than those who did not achieve a complete response beginning at week 12 of peg-IFN-alpha-2a therapy.CONCLUSIONS: TLR8 expression and function in PBMCs were impaired by chronic HBV infection. Higher TLR8 expression after treatment week 12 could potentially predict complete response to peg-IFN-alpha-2a therapy. (C) 2017 Elsevier Masson SAS. All rights reserved.