Targeted Induction of Interferon-λ in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection

被引：37

作者：

Nakagawa, Shin-ichiro ^{[1
,2
]}

Hirata, Yuichi ^{[1
,11
]}

Kameyama, Takeshi ^{[3
]}

Tokunaga, Yuko ^{[1
]}

Nishito, Yasumasa ^{[4
]}

Hirabayashi, Kazuko ^{[2
]}

Yano, Junichi ^{[2
]}

Ochiya, Takahiro ^{[5
]}

Tateno, Chise ^{[6
]}

Tanaka, Yasuhito ^{[7
,8
]}

Mizokami, Masashi ^{[9
]}

Tsukiyama-Kohara, Kyoko ^{[10
]}

Inoue, Kazuaki ^{[11
]}

Yoshiba, Makoto ^{[11
]}

Takaoka, Akinori ^{[3
]}

Kohara, Michinori ^{[1
]}

机构：

[1] Tokyo Metropolitan Inst Med Sci, Dept Microbiol & Cell Biol, Setagaya Ku, Tokyo 113, Japan

[2] Nippon Shinyaku Co Ltd, Discovery Res Labs, Tsukuba, Ibaraki, Japan

[3] Hokkaido Univ, Inst Med Genet, Div Signaling Canc & Immunol, Sapporo, Hokkaido, Japan

[4] Tokyo Metropolitan Inst Med Sci, Ctr Microarray Anal, Setagaya Ku, Tokyo 113, Japan

[5] Japanese Natl Canc Ctr, Res Inst, Div Mol & Cellular Med, Chuo Ku, Tokyo, Japan

[6] PhoenixBio Co Ltd, Hiroshima, Japan

[7] Nagoya City Univ, Dept Virol, Grad Sch Med Sci, Nagoya, Aichi, Japan

[8] Nagoya City Univ, Liver Unit, Grad Sch Med Sci, Nagoya, Aichi, Japan

[9] Japan Konodai Hosp, Res Ctr Hepatitis & Immunol, Int Med Ctr, Ichikawa, Chiba, Japan

[10] Kagoshima Univ, Joint Fac Vet Med, Transboundary Anim Dis Ctr, Kagoshima 890, Japan

[11] Showa Univ, Fujigaoka Hosp, Div Gastroenterol, Yokohama, Kanagawa 227, Japan

来源：

PLOS ONE | 2013年 / 8卷 / 03期

关键词：

HEPATITIS-C VIRUS; TOLL-LIKE RECEPTOR-3; GENOME-WIDE ASSOCIATION; INNATE IMMUNE-RESPONSE; B-VIRUS; GENETIC-VARIATION; LIPOSOME COMPLEX; ADAPTER PROTEIN; CELL-ACTIVITY; IN-VIVO;

D O I：

10.1371/journal.pone.0059611

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background & Aims: 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). Methods: 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. Results: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-lambda s, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-alpha or IFN-beta in these animals. Strong induction of IFN-lambda s 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-lambda 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. Conclusions: 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-lambda s play an important role in the defense against human hepatic virus infection.

引用

页数：12

共 50 条

[11] Human Type 2 Myeloid Dendritic Cells Produce Interferon-λ and Amplify Interferon-α in Response to Hepatitis C Virus Infection [J].

Zhang, Shuye ;

Kodys, Karen ;

Li, Kui ;

Szabo, Gyongyi .

GASTROENTEROLOGY, 2013, 144 (02) :414-+

[12] Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism [J].

De Serres, Mark ;

Bowers, Gary ;

Boyle, Gary ;

Beaumont, Claire ;

Castellino, Steve ;

Sigafoos, James ;

Dave, Mehul ;

Roberts, Andrew ;

Shah, Vishal ;

Olson, Katie ;

Patel, Dipak ;

Wagner, David ;

Yeager, Russell ;

Serabjit-Singh, Cosette .

XENOBIOTICA, 2011, 41 (06) :464-475

[13] Hepatitis C Virus Induces Interferon-λ and Interferon-Stimulated Genes in Primary Liver Cultures [J].

Marukian, Svetlana ;

Andrus, Linda ;

Sheahan, Timothy P. ;

Jones, Christopher T. ;

Charles, Edgar D. ;

Ploss, Alexander ;

Rice, Charles M. ;

Dustin, Lynn B. .

HEPATOLOGY, 2011, 54 (06) :1913-1923

[14] Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection [J].

Hernandez, Pedro P. ;

Mahlakoiv, Tanel ;

Yang, Ines ;

Schwierzeck, Vera ;

Nam Nguyen ;

Guendel, Fabian ;

Gronke, Konrad ;

Ryffel, Bernhard ;

Hoelscher, Christoph ;

Dumoutier, Laure ;

Renauld, Jean-Christophe ;

Suerbaum, Sebastian ;

Staeheli, Peter ;

Diefenbach, Andreas .

NATURE IMMUNOLOGY, 2015, 16 (07) :698-+

[15] Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection [J].

Wang, Kai-Li ;

Xing, Han-Qian ;

Zhao, Hong ;

Liu, Jun-Wei ;

Gao, Deng-Lian ;

Zhang, Xue-Hua ;

Yao, Hong-Yu ;

Yan, Li ;

Zhao, Jun .

WORLD JOURNAL OF GASTROENTEROLOGY, 2014, 20 (14) :4071-4075

[16] Induction of Chemokines by Hepatitis C Virus Proteins: Synergy of the Core Protein with Interleukin-1β and Interferon-γ in Liver Bystander Cells [J].

Salama, Sara Abouelasrar ;

Gouwy, Mieke ;

De Zutter, Alexandra ;

Portner, Noemie ;

Vanbrabant, Lotte ;

Berghmans, Nele ;

De Buck, Mieke ;

Struyf, Sofie ;

Van Damme, Jo .

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2020, 40 (04) :195-206

[17] P450-Humanized and Human Liver Chimeric Mouse Models for Studying Xenobiotic Metabolism and Toxicity [J].

Bissig, Karl-Dimiter ;

Han, Weiguo ;

Barzi, Mercedes ;

Kovalchuk, Nataliia ;

Ding, Liang ;

Fan, Xiaoyu ;

Pankowicz, Francis P. ;

Zhang, Qing-Yu ;

Ding, Xinxin .

DRUG METABOLISM AND DISPOSITION, 2018, 46 (11) :1734-1744

[18] Longterm efficacy of interferon-α for extrahepatic disease associated with hepatitis C virus infection [J].

Naarendorp, M ;

Kallemuchikkal, U ;

Nuovo, GJ ;

Gorevic, PD .

JOURNAL OF RHEUMATOLOGY, 2001, 28 (11) :2466-2473

[19] Differences between interferon-α and -β treatment for patients with chronic hepatitis C virus infection [J].

Furusyo, N ;

Hayashi, J ;

Ohmiya, M ;

Sawayama, Y ;

Kawakami, Y ;

Ariyama, I ;

Kinukawa, N ;

Kashiwagi, S .

DIGESTIVE DISEASES AND SCIENCES, 1999, 44 (03) :608-617

[20] Differences Between Interferon-α and-β Treatment for Patients with Chronic Hepatitis C Virus Infection [J].

Norihiro Furusyo ;

Jun Hayashi ;

Misako Ohmiya ;

Yasunori Sawayama ;

Yasunobu Kawakami ;

Iwao Ariyama ;

Naoko Kinukawa ;

Seizaburo Kashiwagi .

Digestive Diseases and Sciences, 1999, 44 :608-617

← 1 2 3 4 5 →