IFIT3 Is Increased in Serum from Patients with Chronic Hepatitis B Virus (HBV) Infection and Promotes the Anti-HBV Effect of Interferon Alpha via JAK-STAT2 In Vitro.
IFIT3 Is Increased in Serum from Patients with Chronic Hepatitis B Virus (HBV) Infection and Promotes the Anti-HBV Effect of Interferon Alpha via JAK-STAT2 In Vitro.
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慢性乙型肝炎病毒 (HBV) 感染患者血清中 IFIT3 增加，并在体外通过 JAK-STAT2 促进干扰素α的抗 HBV 作用
DOI：
10.1128/spectrum.01557-22
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发表时间：
2022-12-21
影响因子：
3.7
通讯作者：
Ou, Qishui
中科院分区：
文献类型：
--
作者：
Xu, Siyi;Huang, Jinlan;Xun, Zhen;Li, Shiqi;Fu, Ya;Lin, Ni;Wu, Wennan;Chen, Tianbin;Liu, Can;Ou, Qishui
越来越多的证据表明，干扰素α（IFN-α）治疗是慢性乙型肝炎病毒（HBV）的亚组的有效治疗选择。干扰素刺激的基因（ISG）的成员可以抑制各种病毒的复制。探索IFN-α抗病毒活性的作用和机制，首先分析了108名治疗患者的外周血和70个健康对照。在IFN-α和HBV的双重干预下，转录（JAK-STAT）的信号通路也被探讨了治疗个体与对照组相比，IFIT3 mRNA的水平升高（机械上的p <0.0001） ，IFIT3的过表达增强了IFN-α触发的ISG的表达，包括粘液病毒电阻A（MXA）， 2'-5'-橄榄核酸合成酶1（OAS1）和双链RNA的RNA激活蛋白激酶（PKR），而在减少IFIT3表达的细胞中，观察到IFN-α触发的ISG较弱的IFN-α触发ISG。经过验证的小发夹RNA（SHRNA），丙型肝炎表面抗原（HBSAG）的水平，丙型肝炎抗原（HBEAG）和HBV DNA瞬时分泌用PHBV1.2的转染增加了我们的发现。
重要的是，我们的研究为理解干扰素诱导的蛋白质与四肽重复3（IFIT3）的功能和作用的新见解有助于新见解，这是人类肝细胞和肝癌细胞以及肝癌细胞和肝癌细胞中丙型肝炎病毒感染引起的干扰素刺激的基因之一可能有助于确定促进干扰素α效率的靶向基因。
Increasing evidence indicates that interferon alpha (IFN-α) therapy is an effective treatment option for a subgroup of patients with chronic hepatitis B virus (HBV) infection. It has been confirmed that interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), a member of the interferon-stimulated genes (ISGs), could inhibit the replication of various viruses. However, its effect on HBV replication is unclear. The present study sought to explore the role and mechanism of IFIT3 in IFN-α antiviral activities against HBV. IFIT3 mRNA levels in the peripheral blood of 108 treatment-naive patients and 70 healthy controls were analyzed first. The effect of IFIT3 on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway under the dual intervention of IFN-α and HBV was also explored in vitro. Treatment-naive individuals exhibited elevated levels of IFIT3 mRNA compared to the controls (P < 0.0001). Mechanistically, the knockdown of IFIT3 inhibited the phosphorylation of signal transducer and activator of transcription 2 (STAT2), whereas the overexpression of IFIT3 produced the opposite effect in vitro. Meanwhile, the overexpression of IFIT3 enhanced the expression of IFN-α-triggered ISGs, including myxovirus resistance A (MxA), 2′-5′-oligoadenylate synthetase 1 (OAS1), and double-stranded RNA-activated protein kinase (PKR), while a weaker induction of IFN-α-triggered ISGs was observed in ruxolitinib-treated cells. After decreasing IFIT3 expression by validated small hairpin RNAs (shRNAs), the levels of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA secreted by HepG2 cells transiently transfected with the pHBV1.2 plasmid were increased. Our findings suggest that IFIT3 works in a STAT2-dependent manner to promote the antiviral effect of IFN-α through the JAK-STAT pathway in HBV infection in both human hepatocytes and hepatocarcinoma cells. IMPORTANCE Our study contributes new insights into the understanding of the functions and roles of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), which is one of the interferon-stimulated genes induced by hepatitis B virus infection in human hepatocytes and hepatocarcinoma cells, and may help to identify targeted genes promoting the efficacy of interferon alpha.
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影响因子：
6.7
作者：
Kimura, Taishi;Flynn, Claudia T.;Whitton, J. Lindsay
通讯作者：
Whitton, J. Lindsay
影响因子：
6.7
作者：
Li, Dajiang;Swaminathan, Sankar
通讯作者：
Swaminathan, Sankar
下调 IFIT3 可保护肝脏免受缺血再灌注损伤
影响因子：
5.6
作者：
Guan, Ge;Shen, Yuntai;Zang, Yunjin
通讯作者：
Zang, Yunjin
影响因子：
5.4
作者：
Osiowy, Carla;Giles, Elizabeth;Minuk, Gerald Y.
通讯作者：
Minuk, Gerald Y.
影响因子：
5.4
作者：
Schmeisser, H.;Mejido, J.;Zoon, K. C.
通讯作者：
Zoon, K. C.