Tumor necrosis factor-alpha induced by hepatitis B virus core mediating the immune response for hepatitis B viral clearance in mice model
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Mendeley | Further Information

{"title"=>"Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model", "type"=>"journal", "authors"=>[{"first_name"=>"Horng-Tay", "last_name"=>"Tzeng"}, {"first_name"=>"Hwei-Fang", "last_name"=>"Tsai"}, {"first_name"=>"I-Tsu", "last_name"=>"Chyuan"}, {"first_name"=>"Hsiu-Jung", "last_name"=>"Liao"}, {"first_name"=>"Chun-Jen", "last_name"=>"Chen"}, {"first_name"=>"Pei-Jer", "last_name"=>"Chen"}, {"first_name"=>"Ping-Ning", "last_name"=>"Hsu"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"25047809", "isbn"=>"1932-6203 (Electronic) 1932-6203 (Linking)", "issn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0103008"}, "id"=>"4983a589-7119-3290-a47d-801bf767e905", "abstract"=>"Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.", "link"=>"http://www.mendeley.com/research/tumor-necrosis-factoralpha-induced-hepatitis-b-virus-core-mediating-immune-response-hepatitis-b-vira-1", "reader_count"=>19, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>5, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>2, "Other"=>1, "Student > Master"=>1, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>5, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>2, "Other"=>1, "Student > Master"=>1, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>12, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>12}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Japan"=>1, "France"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1603299"], "description"=>"<p>(A) BALB/c mice were hydrodynamiclly injected with pAAV/core-null plasmids, which contain a premature stop codon in the core open reading frame of a replication-competent HBV plasmid pAAV/HBV1.2 on Day 7. At Day 0, purified recombinant HBV core protein was injected hydrodynamically. Etanercept was administered on Days 1, 3, and 5 via intravenous injection. The serum HBsAg level was quantified at the indicated time points with an enzyme immunoassay [calculated as IU/ml]. N = number of mice in each experiment. (B) BALB/c mice were hydrodynamically injected with 10<i> </i>µg of pAAV/core-null plus 10<i> </i>µg of pFLAG-CMV2/HBc in the presence or absence of Etanercept or combined with pFLAG-CMV2/HBcY132A, a capsid assembly-defect mutant <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103008#pone.0103008-Lin2\" target=\"_blank\">[25]</a>. The titers of serum HBsAg were measured at the indicated time points. (C) C57BL/6 and TNF-α knockout mice were hydrodynamically injected with 10<i> </i>µg pAAV/core-null plus 10<i> </i>µg pFLAG-CMV2/HBc. The titers of serum HBsAg were measured [S/N]. (D) Intrahepatic lymphocytes from C57BL/6 mice hydrodynamically injected with pAAV/HBV1.2 or pAAV/core-null plasmid were isolated at 18 days postinjection. The expressions of CD8<sup>+</sup> PD-1<sup>+</sup> (upper panel) or levels of PD-1 or CD127 (lower panel) on CD8 T cells were analyzed by flow cytometry. (E) HBcAg-specific IFN-γ secretion of liver mononuclear cells from mice injected with pAAV/HBV1.2 or pAAV/core-null were analyzed by an ELISpot assay. The frequency of spot-forming cells were measured. Student’s-t test, *p<0.05.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "abolished", "hbcag-induced", "hbsag", "clearance", "mice"], "article_id"=>1112926, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g005", "stats"=>{"downloads"=>1, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_lack_of_TNF_945_abolished_HBcAg_induced_HBsAg_clearance_in_mice_sera_/1112926", "title"=>"A lack of TNF-α abolished HBcAg-induced HBsAg clearance in mice sera.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603296"], "description"=>"<p>(A) BALB/c mice were treated with the recombinant soluble TNF-α receptor, Etanercept, on the day before hydrodynamic injection of the pAAV/HBV1.2 plasmid. Etanercept treatment was performed twice a week over the detection period. HBsAg levels in mice serum were determined by an ELISA. HBsAg-positivity was defined as an S/N ratio greater than 2. Differences in percentages (left) and serum levels (right) of HBsAg-positive mice with or without Etanercept were quantified. (B) Wild type C57BL/6 or TNF-α knockout mice were hydrodynamically transfected with the pAAV/HBV1.2 plasmid. Differences in percentages (left) and serum levels (right) of HBsAg-positive mice were quantified. *<i>p</i><0.05.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "hbsag", "clearance", "mice", "tnf"], "article_id"=>1112923, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g002", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Delayed_HBsAg_clearance_in_mice_with_TNF_deficiency_/1112923", "title"=>"Delayed HBsAg clearance in mice with TNF deficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603295"], "description"=>"<p>Wild type C57BL/6 and different knockout mice, including NLRP3, apoptosis- ASC, MYD88, IL-1R, IFNAR, RIG-1, MAD5, and TNF-α, were introduced to the pAAV/HBV1.2 plasmid by hydrodynamic injection. HBsAg levels in mice serum were determined by an ELISA. HBsAg-positivity was defined as an S/N ratio greater than 2. The percentage of HBsAg-positivity (A) and serum HBsAg levels (B) were measured at Weeks 1, 3, 6 and 8. #, not detectable.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "hbv", "persistence", "knockout"], "article_id"=>1112922, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Prolonged_HBV_persistence_in_TNF_945_knockout_mice_/1112922", "title"=>"Prolonged HBV persistence in TNF-α knockout mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603298"], "description"=>"<p>(A) BALB/c mice with or without Etanercept treatment (upper panel) and TNF-α knockout mice (lower panel) were hydrodynamically injected with pAAV/HBV1.2. The serum HBV DNA in mice was quantified by real-time PCR at the indicated time points. The detection limit for HBV DNA in our system was 1000 copies per milliliter. (B) Liver samples were collected from Etanercept-treated BLAB/c and TNF-α knockout mice on Days 3 and 42 after pAAV/HBV1.2 hydrodynamic injection to examine viral replication, transcription, and HBcAg expression. Intrahepatic HBV DNA and viral transcripts were detected by Southern and Northern blotting, respectively, and GAPDH mRNA was shown as a loading control. The expressions of HBcAg and β-actin (loading control) were analyzed by SDS-PAGE followed by Western blotting. (C) Immunohistochemical staining for expressing HBcAg and HBsAg in the livers of Etanercept-treated BALB/c mice and TNF-α knockout mice compared to C57BL/6 (WT) mice on Days 3 and 42 after pAAV/HBV1.2 injection. *<i>p</i><0.05.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "clearance", "serum", "hbv", "dna", "viral", "mice", "tnf"], "article_id"=>1112925, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g004", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Delayed_clearance_of_serum_HBV_DNA_and_increased_viral_gene_expression_in_mice_with_TNF_deficiency_/1112925", "title"=>"Delayed clearance of serum HBV DNA and increased viral gene expression in mice with TNF deficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603297"], "description"=>"<p>(A) BALB/c mice were hydrodynamically injected with WT pAAV/HBV1.2 plasmids in the presence or absence of Etanercept treatment. Eight weeks after injection, intrahepatic lymphocytes from HBsAg-positive mice were isolated and the PD-1, CD127 expressions of liver-infiltrating CD8<sup>+</sup> lymphocytes and splenocytes were analyzed by flow cytometry. (B) Wild type C57BL/6 and TNF-α knockout mice were hydrodynamically injected with WT pAAV/HBV1.2 plasmids. Eight weeks after the injection, intrahepatic lymphocytes from HBsAg-positive mice were isolated and the PD-1, CD127 expressions by liver-infiltrating CD8<sup>+</sup> lymphocytes and splenocytes were analyzed by flow cytometry. (C) Wild type C57BL/6 and TNF-α knockout mice as well as BALB/c mice with or without Etanercept treatment were hydrodynamically injected with pAAV/HBV1.2. Fourteen days after the injection, liver mononuclear cells (LMNCs) were isolated and HBcAg-specific IFN-γ responses were analyzed by an ELISpot assay. The frequency of HBcAg-specific IFN-γ-secretion was measured as spot-forming cells per 10<sup>5</sup> LMNCs. *<i>p</i><0.05. The data are representative of at least six independent experiments.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "lymphocytes", "etanercept-treated", "knockout", "mice", "displayed", "phenotype", "impaired", "hbcag-specific"], "article_id"=>1112924, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g003", "stats"=>{"downloads"=>1, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_infiltrating_CD8_lymphocytes_in_Etanercept_treated_and_TNF_945_knockout_mice_displayed_the_PD_1_hi_CD127_low_exhausted_phenotype_and_impaired_HBcAg_specific_IFN_947_T_cell_response_/1112924", "title"=>"Liver-infiltrating CD8<sup>+</sup> lymphocytes in Etanercept-treated and TNF-α knockout mice displayed the PD-1<sup>hi</sup>CD127<sup>low</sup>-exhausted phenotype and impaired HBcAg-specific IFN-γ T cell response.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603302", "https://ndownloader.figshare.com/files/1603303", "https://ndownloader.figshare.com/files/1603304", "https://ndownloader.figshare.com/files/1603305"], "description"=>"<div><p>Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8<sup>+</sup> T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.</p></div>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "necrosis", "factor-alpha", "induced", "hepatitis", "mediating", "viral", "clearance", "mice"], "article_id"=>1112929, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0103008.s001", "https://dx.doi.org/10.1371/journal.pone.0103008.s002", "https://dx.doi.org/10.1371/journal.pone.0103008.s003", "https://dx.doi.org/10.1371/journal.pone.0103008.s004"], "stats"=>{"downloads"=>8, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tumor_Necrosis_Factor_Alpha_Induced_by_Hepatitis_B_Virus_Core_Mediating_the_Immune_Response_for_Hepatitis_B_Viral_Clearance_in_Mice_Model_/1112929", "title"=>"Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-07-21 14:48:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1603300"], "description"=>"<p>(A). C57BL/6 mice received pAAV/HBV1.2 or pAAV/core-null plasmids by hydrodynamic injection into a tail vein. At Day 3 post-injection, hepatocytes were isolated and cultured for 24<i> </i>h. The secretory level of HBsAg and intracellular HBcAg expression were determined by enzyme immunoassay (upper left panel) and Western blotting (upper right panel), respectively. After 24<i> </i>h of hepatocyte incubation, the intra hepatic leukocytes were isolated from naïve syngenic mice and co-cultured with hepatocytes for a further 12 or 24<i> </i>h. The TNF-α production in culture medium was measured by ELISA assay. (B) Wild-type C57BL/6 or TNF-α knockout mice were injected hydrodynamically with pAAV/HBV1.2 plasmids. Hepatocytes were isolated and cultured for 24<i> </i>h. Naïve intra hepatic leukocytes were isolated from wild-type C57BL/6 or TNF-α knockout mice and incubated with hepatocytes for 24<i> </i>h. The TNF-α level in culture supernatants was determined by ELISA assay.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "Gastroenterology and hepatology", "hepatic", "leukocytes", "hbcag-induced"], "article_id"=>1112927, "categories"=>["Biological Sciences"], "users"=>["Horng-Tay Tzeng", "Hwei-Fang Tsai", "I-Tsu Chyuan", "Hsiu-Jung Liao", "Chun-Jen Chen", "Pei-Jer Chen", "Ping-Ning Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103008.g006", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intra_hepatic_leukocytes_were_responsible_for_HBcAg_induced_TNF_production_in_an_ex_vivo_culture_system_/1112927", "title"=>"Intra hepatic leukocytes were responsible for HBcAg-induced TNF-α production in an <i>ex vivo</i> culture system.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-21 14:48:09"}

PMC Usage Stats | Further Information

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Relative Metric

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