Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.
Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.
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DOI：
10.1371/journal.pone.0059611
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kohara M
中科院分区：
文献类型：
--
作者：
Nakagawa S;Hirata Y;Kameyama T;Tokunaga Y;Nishito Y;Hirabayashi K;Yano J;Ochiya T;Tateno C;Tanaka Y;Mizokami M;Tsukiyama-Kohara K;Inoue K;Yoshiba M;Takaoka A;Kohara M
干扰素（IFN）系统在先天性抗病毒应答中起关键作用。我们推测IFN在人肝脏中的靶向诱导对丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）显示出强大的抗病毒作用。这项研究使用了携带人源化肝脏并感染HCV或HBV的嵌合小鼠。该小鼠模型允许同时分析同一肝脏中人和小鼠肝细胞的免疫应答，并探索抗这些病毒的抗病毒作用机制。通过用包含亲肝阳离子脂质体和合成的双链RNA类似物pIC（LIC-pIC）的复合物处理动物来诱导IFN的靶向表达。在这些人源化嵌合小鼠的肝脏和血清中分析病毒复制、IFN基因表达、IFN蛋白产生和IFN抗病毒活性（对于I、II和III型IFN）。用LIC-pIC处理后，嵌合小鼠的人源化肝脏显示出人IFN-λ s的表达增加（在mRNA和蛋白水平），导致对HBV和HCV的强抗病毒作用。在这些动物中未观察到人IFN-α或IFN-β的类似增加。LIC-pIC对IFN-λ的强诱导仅发生在人肝细胞中，而不在小鼠肝细胞中，也不在来自其他（非肝）组织的人细胞系中。LIC-pIC诱导的IFN-λ产生由免疫传感器适配器分子线粒体抗病毒信号蛋白（MAVS）和Toll/IL-1R结构域含有适配器分子-1（TICAM-1）介导，表明LIC-pIC通过两种传感器适配器途径双重识别。这些发现表明，各种IFN的表达和功能根据所研究的动物物种和组织而不同。人源化肝嵌合小鼠的研究表明，IFN-λ在抗人肝病毒感染中发挥重要作用。
The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
影响因子：
2.2
作者：
Kashiwakuma, T;Hasegawa, A;Kohara, M
通讯作者：
Kohara, M
影响因子：
30.8
作者：
Prokunina-Olsson, Ludmila;Muchmore, Brian;Tang, Wei;Pfeiffer, Ruth M.;Park, Heiyoung;Dickensheets, Harold;Hergott, Dianna;Porter-Gill, Patricia;Mumy, Adam;Kohaar, Indu;Chen, Sabrina;Brand, Nathan;Tarway, McAnthony;Liu, Luyang;Sheikh, Faruk;Astemborski, Jacquie;Bonkovsky, Herbert L.;Edlin, Brian R.;Howell, Charles D.;Morgan, Timothy R.;Thomas, David L.;Rehermann, Barbara;Donnelly, Raymond P.;O'Brien, Thomas R.
通讯作者：
O'Brien, Thomas R.
影响因子：
29.4
作者：
Rauch, Andri;Kutalik, Zoltan;Bochud, Pierre-Yves
通讯作者：
Bochud, Pierre-Yves