State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Infectious Diseases, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China.
Viral Immunol. 2020 Dec;33(10):642-651. doi: 10.1089/vim.2020.0096. Epub 2020 Nov 10.
DNA-dependent activator of interferon regulatory factors (DAIs), interferon gamma inducible protein 16 (IFI16), DEAD-box polypeptide 41 (DDX41), DNA-dependent protein kinase (DNA-PK), meiotic recombination 11 homolog A (MRE11), and cyclic GMP-AMP synthase (cGAS) have been identified as intracellular STING-dependent DNA sensors in recent years. Studies have shown that the DNA sensor-STING-interferon (IFN)- pathway plays an important role in the defense against intracellular invasion of many DNA viruses. However, the intracellular recognition of hepatitis B virus (HBV) DNA by DNA sensors is still largely unclear. In this study, we aimed to determine whether the DNA sensor-STING pathway in peripheral blood mononuclear cells (PBMCs) can be activated by acute and chronic HBV infections in humans. We first evaluated the expression of these DNA sensors in PBMCs of acute and chronic HBV-infected patients by quantitative real-time polymerase chain reaction. We next compared the expression of the upregulated DNA sensor between monocytes and nonmonocytes to find its cellular source. Finally, by stimulation, we analyzed the IFN- response of the DNA sensor-STING pathway in PBMCs and monocytes from chronic HBV-infected patients. The results showed that IFI16, DDX41, MRE11, and the adaptor STING were upregulated in chronic HBV-infected patients, whereas only IFI16 was upregulated in acute HBV-infected patients. However, IFN- expression was not changed in PBMCs from acute and chronic HBV-infected patients. We next found IFI16 was mainly expressed in monocytes of acute and chronic hepatitis B patients. Finally, by stimulation of monocytes with VACV ds 70mer, a ligand for IFI16, we confirmed the attenuated response of the IFI16-STING pathway. Taken together, our results suggest that HBV might be sensed by DNA sensors in PBMCs of acute and chronic HBV-infected patients, and meanwhile HBV infection attenuates the response of the DNA sensor-STING pathway in PBMCs and monocytes, which may facilitate the persistence of HBV infection.
近年来，人们已经发现了一些依赖 DNA 的干扰素调节因子激活物（DAIs），如干扰素 γ诱导蛋白 16（IFI16）、DEAD 框多肽 41（DDX41）、DNA 依赖性蛋白激酶（DNA-PK）、有丝分裂重组 11 同源物 A（MRE11）和环鸟苷酸-腺苷酸合酶（cGAS），它们是细胞内 STING 依赖性 DNA 传感器。研究表明，DNA 传感器-STING-干扰素（IFN）途径在抵抗多种 DNA 病毒的细胞内入侵中起着重要作用。然而，HBV 感染细胞内的 DNA 传感器的识别仍很大程度上不清楚。在这项研究中，我们旨在确定外周血单个核细胞（PBMCs）中的 DNA 传感器-STING 途径是否可被急性和慢性 HBV 感染激活。我们首先通过定量实时聚合酶链反应评估了急性和慢性 HBV 感染患者 PBMC 中这些 DNA 传感器的表达。接下来，我们比较了单核细胞和非单核细胞之间上调的 DNA 传感器的表达，以找到其细胞来源。最后，通过刺激，我们分析了慢性 HBV 感染患者 PBMC 和单核细胞中 DNA 传感器-STING 途径的 IFN-反应。结果显示，慢性 HBV 感染患者中 IFI16、DDX41、MRE11 和衔接蛋白 STING 上调，而急性 HBV 感染患者仅 IFI16 上调。然而，急性和慢性 HBV 感染患者的 PBMC 中 IFN-表达未改变。我们发现 IFI16 主要在急性和慢性乙型肝炎患者的单核细胞中表达。最后，通过用 VACV ds70mer 刺激单核细胞，一种 IFI16 的配体，我们证实了 IFI16-STING 途径的反应减弱。总之，我们的结果表明，HBV 可能在急性和慢性 HBV 感染患者的 PBMCs 中被 DNA 传感器检测到，同时 HBV 感染减弱了 PBMCs 和单核细胞中 DNA 传感器-STING 途径的反应，这可能有助于 HBV 感染的持续存在。
