Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.
Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.
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DOI：
10.1038/nm.4211
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发表时间：
2016-12
期刊：
影响因子：
82.9
通讯作者：
Savan R
中科院分区：
文献类型：
--
作者：
Jarret A;McFarland AP;Horner SM;Kell A;Schwerk J;Hong M;Badil S;Joslyn RC;Baker DP;Carrington M;Hagedorn CH;Gale M Jr;Savan R
丙型肝炎病毒（HCV）感染全球2亿人，60-80%的病例持续为慢性感染，2-10%的患者将进展为肝硬化和肝癌。我们最近证明，HCV诱导两种宿主microRNA（miRNA），miR-208 b和miR-499 a-5 p，在感染的肝细胞中由肌球蛋白基因编码的异常表达。这些miRNAs，沿着富含AU的元件介导的衰变，抑制IFNL 2和IFNL 3（III型干扰素（IFN）基因家族的成员），以支持病毒持续存在。在这项研究中，我们发现miR-208 b和miR-499 a-5 p也通过直接下调I型IFN受体链IFNAR 1的表达来抑制HCV感染肝细胞中的I型IFN信号传导。在HCV感染期间通过使用miRNA抑制剂抑制这些miRNA增加IFNAR 1的表达。此外，抑制拯救了外源性I型IFN的抗病毒反应，如通过IFN刺激基因的显著增加和HCV载量的减少所测量的。与单独HCV感染相比，用I型IFN治疗HCV感染的肝细胞增加肌球蛋白的表达。由于这些miRNA可以抑制III型IFN家族成员，这些数据共同定义了HCV感染期间I型和III型IFN之间的新交叉调节。
Hepatitis C virus (HCV) infects 200 million people globally, and 60–80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2–10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
30.5
作者：
McFarland, Addle P.;Horner, Stacy M.;Jarret, Abigail;Joslyn, Rochelle C.;Bindewald, Eckart;Shapiro, Bruce A.;Delker, Don A.;Hagedorn, Curt H.;Carrington, Mary;Gale, Michael, Jr.;Savan, Ram
通讯作者：
Savan, Ram
影响因子：
13.5
作者：
Ghany, Marc G.;Nelson, David R.;Strader, Doris B.;Thomas, David L.;Seeff, Leonard B.
通讯作者：
Seeff, Leonard B.
影响因子：
6
作者：
Chandra, Partha K.;Bao, Lili;Dash, Srikanta
通讯作者：
Dash, Srikanta
影响因子：
13.5
作者：
di Iulio, Julia;Ciuffi, Angela;Rauch, Andri
通讯作者：
Rauch, Andri