Targeted Induction of Interferon-λ in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection
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Mendeley | Further Information

{"title"=>"Targeted Induction of Interferon-λ in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection", "type"=>"journal", "authors"=>[{"first_name"=>"Shin ichiro", "last_name"=>"Nakagawa", "scopus_author_id"=>"35474113500"}, {"first_name"=>"Yuichi", "last_name"=>"Hirata", "scopus_author_id"=>"26635190500"}, {"first_name"=>"Takeshi", "last_name"=>"Kameyama", "scopus_author_id"=>"24822267400"}, {"first_name"=>"Yuko", "last_name"=>"Tokunaga", "scopus_author_id"=>"36762261500"}, {"first_name"=>"Yasumasa", "last_name"=>"Nishito", "scopus_author_id"=>"6603115659"}, {"first_name"=>"Kazuko", "last_name"=>"Hirabayashi", "scopus_author_id"=>"36859949500"}, {"first_name"=>"Junichi", "last_name"=>"Yano", "scopus_author_id"=>"7101761244"}, {"first_name"=>"Takahiro", "last_name"=>"Ochiya", "scopus_author_id"=>"7003487576"}, {"first_name"=>"Chise", "last_name"=>"Tateno", "scopus_author_id"=>"6701349148"}, {"first_name"=>"Yasuhito", "last_name"=>"Tanaka", "scopus_author_id"=>"7405315865"}, {"first_name"=>"Masashi", "last_name"=>"Mizokami", "scopus_author_id"=>"56490052300"}, {"first_name"=>"Kyoko", "last_name"=>"Tsukiyama-Kohara", "scopus_author_id"=>"6603893036"}, {"first_name"=>"Kazuaki", "last_name"=>"Inoue", "scopus_author_id"=>"56484937300"}, {"first_name"=>"Makoto", "last_name"=>"Yoshiba", "scopus_author_id"=>"55741407600"}, {"first_name"=>"Akinori", "last_name"=>"Takaoka", "scopus_author_id"=>"56622562000"}, {"first_name"=>"Michinori", "last_name"=>"Kohara", "scopus_author_id"=>"55362962600"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84875525938", "pui"=>"368612327", "doi"=>"10.1371/journal.pone.0059611", "pmid"=>"23555725", "scopus"=>"2-s2.0-84875525938", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"544f0210-1c33-3792-abda-1e5359500c76", "abstract"=>"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).\\n\\nMETHODS: 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.\\n\\nRESULTS: 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.\\n\\nCONCLUSIONS: 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.", "link"=>"http://www.mendeley.com/research/targeted-induction-interferon%CE%BB-humanized-chimeric-mouse-liver-abrogates-hepatotropic-virus-infection", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>8, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>8, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>4, "Philosophy"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Philosophy"=>{"Philosophy"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>1, "Japan"=>1, "United Kingdom"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1000360"], "description"=>"<p>(<b>A</b>) Experimental schedule in chimeric mice infected with HCV. (<b>B</b>) Serum concentrations (in chimeric mice) of human and mouse IFN-β and IFN-α, as determined by ELISA (<i>n</i> = 3–5 for no treatment or LIC-pIC group; <i>n</i> = 6–8 for PegIFN-α group). Bars indicate the mean concentration of human (red) and mouse (green) IFNs averaged across the entire group. The results indicates the representative of two measurements (<b>C</b>) The liver mRNA levels of genes encoding IFN-β, IFN-α2 and IFN-γ (human genes: <i>IFNB1</i>, <i>IFNA2</i> and <i>IFNG</i>, respectively; mouse genes: <i>Ifnb1</i>, <i>Ifna2</i> and <i>Ifng</i>, respectively), as determined by qRT-PCR (<i>n</i> = 3–4 per group). The bars indicate the mean mRNA levels of human (red) and mouse (green) IFN genes averaged across the entire group. The results indicates the representative of two measurements (<b>D</b>) Effectiveness of recombinant human or mouse IFN-β against HCV in FLR 3-1 HCV-replicon cells. The bars indicate SD (<i>n</i> = 4 per group). **<i>P</i><0.01, treatments vs. the vehicle by Dunnett’s multiple comparison test.</p>", "links"=>[], "tags"=>["genes", "encoding", "induction", "lic-pic", "chimeric", "mice", "humanized"], "article_id"=>662072, "categories"=>["Biological Sciences", "Chemistry", "Infectious Diseases", "Immunology"], "users"=>["Shin-ichiro Nakagawa", "Yuichi Hirata", "Takeshi Kameyama", "Yuko Tokunaga", "Yasumasa Nishito", "Kazuko Hirabayashi", "Junichi Yano", "Takahiro Ochiya", "Chise Tateno", "Yasuhito Tanaka", "Masashi Mizokami", "Kyoko Tsukiyama-Kohara", "Kazuaki Inoue", "Makoto Yoshiba", "Akinori Takaoka", "Michinori Kohara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0059611.g002", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_genes_encoding_IFN_945_IFN_946_and_IFN_947_following_induction_by_LIC_pIC_in_chimeric_mice_with_humanized_livers_/662072", "title"=>"Expression of genes encoding IFN-α, IFN-β, and IFN-γ following induction by LIC-pIC in chimeric mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-29 10:24:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1000363", "https://ndownloader.figshare.com/files/1000364", "https://ndownloader.figshare.com/files/1000365", "https://ndownloader.figshare.com/files/1000367", "https://ndownloader.figshare.com/files/1000368", "https://ndownloader.figshare.com/files/1000369", "https://ndownloader.figshare.com/files/1000370", "https://ndownloader.figshare.com/files/1000371", "https://ndownloader.figshare.com/files/1000372", "https://ndownloader.figshare.com/files/1000373", "https://ndownloader.figshare.com/files/1000374", "https://ndownloader.figshare.com/files/1000375"], "description"=>"<div><p>Background & Aims</p><p>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).</p> <p>Methods</p><p>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.</p> <p>Results</p><p>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.</p> <p>Conclusions</p><p>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.</p> </div>", "links"=>[], "tags"=>["induction", "humanized", "chimeric", "abrogates", "hepatotropic"], "article_id"=>662075, "categories"=>["Biological Sciences", "Chemistry", "Infectious Diseases", "Immunology"], "users"=>["Shin-ichiro Nakagawa", "Yuichi Hirata", "Takeshi Kameyama", "Yuko Tokunaga", "Yasumasa Nishito", "Kazuko Hirabayashi", "Junichi Yano", "Takahiro Ochiya", "Chise Tateno", "Yasuhito Tanaka", "Masashi Mizokami", "Kyoko Tsukiyama-Kohara", "Kazuaki Inoue", "Makoto Yoshiba", "Akinori Takaoka", "Michinori Kohara"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0059611.s001", "https://dx.doi.org/10.1371/journal.pone.0059611.s002", "https://dx.doi.org/10.1371/journal.pone.0059611.s003", "https://dx.doi.org/10.1371/journal.pone.0059611.s004", "https://dx.doi.org/10.1371/journal.pone.0059611.s005", "https://dx.doi.org/10.1371/journal.pone.0059611.s006", "https://dx.doi.org/10.1371/journal.pone.0059611.s007", "https://dx.doi.org/10.1371/journal.pone.0059611.s008", "https://dx.doi.org/10.1371/journal.pone.0059611.s009", "https://dx.doi.org/10.1371/journal.pone.0059611.s010", "https://dx.doi.org/10.1371/journal.pone.0059611.s011", "https://dx.doi.org/10.1371/journal.pone.0059611.s012"], "stats"=>{"downloads"=>14, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Targeted_Induction_of_Interferon_955_in_Humanized_Chimeric_Mouse_Liver_Abrogates_Hepatotropic_Virus_Infection_/662075", "title"=>"Targeted Induction of Interferon-λ in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-03-29 10:27:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1000361"], "description"=>"<p>(<b>A</b>) Experimental schedule in the chimeric mice infected with HCV. (<b>B</b>) Microarray analysis of IFN family gene expression. Log<sub>2</sub> ratio values of gene expression were calculated with respect to control (untreated and HCV-infected) chimeric mice<b>.</b> (<b>C</b>) Liver mRNA levels of human IFN genes (<i>n</i> = 3–5 per group), as determined by qRT-PCR. (<b>D</b>) Serum concentration of human IFN-λ1, IFN-λ2, IFN-β, and IFN-α (<i>n</i> = 3 per group), as determined by ELISA. (<b>E</b>) Serum HCV RNA levels, relative to the baseline, in HCV-infected chimeric mice treated with human IFN-λ, LIC-pIC, or control saline (<i>n</i> = 3–5 per group), as determined by qRT-PCR. (<b>F</b>) The HCV RNA levels in the serum and liver of HCV genotype 1a-infected chimeric mice collected on Day 4 of LIC-pIC treatment, as determined by qRT-PCR. The mice were additionally treated with either a control antibody or a neutralizing antibody against IFN-λ (<i>n</i> = 3 per group). Bars indicate SD. **<i>P</i><0.01, treatments vs. saline controls on the respective day, by Dunnett’s multiple comparison test.</p>", "links"=>[], "tags"=>["induction", "innate", "immunity"], "article_id"=>662073, "categories"=>["Biological Sciences", "Chemistry", "Infectious Diseases", "Immunology"], "users"=>["Shin-ichiro Nakagawa", "Yuichi Hirata", "Takeshi Kameyama", "Yuko Tokunaga", "Yasumasa Nishito", "Kazuko Hirabayashi", "Junichi Yano", "Takahiro Ochiya", "Chise Tateno", "Yasuhito Tanaka", "Masashi Mizokami", "Kyoko Tsukiyama-Kohara", "Kazuaki Inoue", "Makoto Yoshiba", "Akinori Takaoka", "Michinori Kohara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0059611.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IFN_expression_following_induction_of_innate_immunity_by_LIC_pIC_/662073", "title"=>"IFN expression following induction of innate immunity by LIC-pIC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-29 10:25:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1000362"], "description"=>"<p>(<b>A</b>, <b>B</b>) The indicated cell lines were stimulated by exposure to LIC-pIC (1 µg/ml). (<b>A</b>) The mRNA levels of IFN-β- and IFN-λ1-encoding genes (<i>IFNB1</i> and <i>IFNL1</i> (<i>IL29</i>), respectively) before and after (12 h) stimulation, as determined by qRT-PCR. (<b>B</b>) The concentration of IFN-λ1 (IL-29) in the culture medium 24 h after stimulation, as determined by ELISA. (<b>C</b>, <b>D</b>) The indicated cell lines were stimulated by viral infection with NDV or VSV. (<b>C</b>) The mRNA levels of IFN-β- and IFN-λ1-encoding genes (<i>IFNB1</i> and <i>IFNL1</i> (<i>IL29</i>), respectively) in HepG2 cells and MRC-5 cells in the absence or presence (12 h) of NDV or VSV, as determined by qRT-PCR. (<b>D</b>) The concentration of IFN-λ1 protein in the culture medium at 24 h post-infection, as determined by ELISA. (<b>E</b>, <b>F</b>) Expression in HepG2 cells of genes encoding MAVS, TICAM-1, and IFN-λ1 (<i>MAVS, TICAM1,</i> and <i>IFNL1</i> (<i>IL29</i>) respectively), as determined by qRT-PCR, after 12 h stimulation with LIC-pIC (1 µg/ml). Cells were pre-treated for 48 h with siRNAs against <i>MAVS</i>, <i>TICAM-1</i>, or a non-target control. Bars indicate SD (<i>n</i> = 3 per group). (<b>G</b>) Schematic outline of the proposed mechanism of the antiviral response induced by LIC-pIC.</p>", "links"=>[], "tags"=>["lines", "induction", "innate", "immunity"], "article_id"=>662074, "categories"=>["Biological Sciences", "Chemistry", "Infectious Diseases", "Immunology"], "users"=>["Shin-ichiro Nakagawa", "Yuichi Hirata", "Takeshi Kameyama", "Yuko Tokunaga", "Yasumasa Nishito", "Kazuko Hirabayashi", "Junichi Yano", "Takahiro Ochiya", "Chise Tateno", "Yasuhito Tanaka", "Masashi Mizokami", "Kyoko Tsukiyama-Kohara", "Kazuaki Inoue", "Makoto Yoshiba", "Akinori Takaoka", "Michinori Kohara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0059611.g004", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IFN_expression_in_cell_lines_following_the_induction_of_innate_immunity_by_various_stimuli_/662074", "title"=>"IFN expression in cell lines following the induction of innate immunity by various stimuli.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-29 10:25:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1000359"], "description"=>"<p>(<b>A</b>, <b>B</b>) Serum HCV RNA levels, relative to the baseline, in HCV genotype 1b-infected (<b>A</b>) or 1a-infected (<b>B</b>) chimeric mice following the indicated treatments, as determined by qRT-PCR (<i>n</i> = 3–5 per group). (<b>C</b>) Liver HCV RNA levels on Day 4 of LIC-pIC treatment (0.1 mg/kg/day), as determined by qRT-PCR. (<b>D</b>) Immunostained liver tissues of HCV genotype 1b-infected chimeric mice treated with saline (Upper) and LIC-pIC (0.1 mg/kg/day) (Lower) at Day 4. (<b>E</b>) Serum HBV DNA levels relative to the baseline following the indicated treatments, as determined by qPCR (<i>n</i> = 3–4 per group). (<b>F</b>) HBV DNA levels of chimeric mouse livers following LIC-pIC treatment, as determined by qPCR (<i>n</i> = 1 per each time point, the results indicates the mean of two measurements) (<b>G</b>) HCV RNA levels relative to the baseline following the indicated treatments, as determined by qRT-PCR (<i>n</i> = 3–4 per group). In all cases, bars indicate SD. **<i>P</i><0.01, treatment vs. saline control by Dunnett’s multiple comparison test.</p>", "links"=>[], "tags"=>["responses", "elicited", "lic-pic", "chimeric", "mice", "humanized"], "article_id"=>662071, "categories"=>["Biological Sciences", "Chemistry", "Infectious Diseases", "Immunology"], "users"=>["Shin-ichiro Nakagawa", "Yuichi Hirata", "Takeshi Kameyama", "Yuko Tokunaga", "Yasumasa Nishito", "Kazuko Hirabayashi", "Junichi Yano", "Takahiro Ochiya", "Chise Tateno", "Yasuhito Tanaka", "Masashi Mizokami", "Kyoko Tsukiyama-Kohara", "Kazuaki Inoue", "Makoto Yoshiba", "Akinori Takaoka", "Michinori Kohara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0059611.g001", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiviral_responses_elicited_by_LIC_pIC_in_chimeric_mice_with_humanized_livers_/662071", "title"=>"Antiviral responses elicited by LIC-pIC in chimeric mice with humanized livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-29 10:24:41"}

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Relative Metric

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