Fine Tuning of a Type 1 Interferon Antagonist
Publication Date
July 09, 2015
Journal
PLOS ONE
Authors
Victoria Urin, Doron Levin, Nanaocha Sharma, Daniel Harari, et al
Volume
10
Issue
7
Pages
e0130797
DOI
https://dx.plos.org/10.1371/journal.pone.0130797
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0130797
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26158644
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497658
Europe PMC
http://europepmc.org/abstract/MED/26158644
Web of Science
000358161200018
Scopus
84941350329
Mendeley
http://www.mendeley.com/research/fine-tuning-type-1-interferon-antagonist
Events
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Mendeley | Further Information

{"title"=>"Fine tuning of a type 1 interferon antagonist", "type"=>"journal", "authors"=>[{"first_name"=>"Victoria", "last_name"=>"Urin", "scopus_author_id"=>"56835560300"}, {"first_name"=>"Doron", "last_name"=>"Levin", "scopus_author_id"=>"45861205400"}, {"first_name"=>"Nanaocha", "last_name"=>"Sharma", "scopus_author_id"=>"55576622100"}, {"first_name"=>"Daniel", "last_name"=>"Harari", "scopus_author_id"=>"57192685609"}, {"first_name"=>"Gideon", "last_name"=>"Schreiber", "scopus_author_id"=>"55861495100"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "pmid"=>"26158644", "doi"=>"10.1371/journal.pone.0130797", "pui"=>"605951988", "issn"=>"19326203", "sgr"=>"84941350329", "scopus"=>"2-s2.0-84941350329"}, "id"=>"d7bd088b-fbfb-384a-9b40-4abb460fa49b", "abstract"=>"Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.", "link"=>"http://www.mendeley.com/research/fine-tuning-type-1-interferon-antagonist", "reader_count"=>13, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>6, "Veterinary Science and Veterinary Medicine"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2169208"], "description"=>"<p>Antagonist activity in mice was determined by their ability to induce or inhibit IFN-induced gene production 3 hours after injection. (A) WT C57bl/6 mice were injected with 1 μg of human (Hu) or mouse (m) IFNβ or 50 μg of each of the antagonists (1ant stands for IFN-1ant and the other antagonists are on top of the 1ant mutations). qPCR of the liver cDNA was performed to evaluate the gene induction levels of three robust (MX1, OAS2 and IFIT1) and two tunable (CXCL10 and CXCL11) genes. (B) WT C57bl/6 mice were injected I.P. with mIFNβ alone or in combination together with 50 μg of each of the antagonist. (C) HyBNAR mice were injected with 50 μg IFN-1ant, 1 μg HuIFNβ or a combination of the two. (D) Statistical analysis of the results in panel B (for genes that are differentially regulated by IFNβ versus IFN-1ant—marked in red) using Anova and Tukey post hoc test. Bars show mean difference between the treatments and error bars show 0.05 confidence intervals between the different treatments. The confidence interval for IFNβ vs combination is 0.005.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478363, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g008", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antagonist_activity_in_mice_/1478363", "title"=>"Antagonist activity in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169207"], "description"=>"<p>Comparing –ΔC<sub>T</sub> (A) to ΔΔC<sub>T</sub> (B) values of IFN induced tunable (upper) and robust (lower) genes. The cells were treated with 200 nM antagonists, 1nM YNS or not treated (0). The data were analyzed with the NetWalker analysis tool [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.ref031\" target=\"_blank\">31</a>].</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478362, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g007", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_C_T_and_916_916_C_T_of_robust_and_tunable_genes_/1478362", "title"=>"–ΔC<sub>T</sub> and ΔΔC<sub>T</sub> of robust and tunable genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169202"], "description"=>"<p>WISH cells were treated with either 200 nM antagonist or 1 nM YNS for 30 minutes and analyzed for levels of STAT1 and STAT2 phosphorylation by western blot assay using specific antibodies in comparison to total protein levels. Total and pSTAT2 levels upon 1 nM of YNS or IFNα2 are shown in the middle panel. pSTAT1 levels for these two proteins were previously shown [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.ref030\" target=\"_blank\">30</a>]. The blot was quantified using the Image Studio Lite software. The results were normalized using 1nM YNS as 100% phosphorylation and the non-treated as 0% (lower panel). The error bars are SE from three independent experiments.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478357, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g004", "stats"=>{"downloads"=>3, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_STAT1_and_STAT2_activation_by_the_IFN_antagonists_/1478357", "title"=>"STAT1 and STAT2 activation by the IFN antagonists.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169201"], "description"=>"<p>(A) WISH cells were treated with the antagonists, YNS, IFNα2 or left untreated for four hours. VSV virus was added for 18 hours, which after cell survival was monitored by crystal violet staining. (B) OVCAR3 cells were treated with the antagonists, YNS, IFNα2 or left untreated for four hours. EMCV virus was added for 23 hours, which after cell survival was monitored by crystal violet staining. The experiments were performed 3 times and the fitting results (for the amplitude) are reported in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.t001\" target=\"_blank\">Table 1</a>. (C) Reduction in antiviral activity upon combined treatment of WISH cells with 200 nM antagonists combined with 0.0001–100 pM IFNα2.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478356, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiviral_activity_of_IFN_antagonists_in_WISH_and_OVCAR3_cells_/1478356", "title"=>"Antiviral activity of IFN antagonists in WISH and OVCAR3 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169209"], "description"=>"<p><i>k</i><sub>a</sub>, <i>k</i><sub>d</sub>, and <i>K</i><sub>D</sub> values were determined using the XPR36 from measurements of six different protein concentrations as shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.g001\" target=\"_blank\">Fig 1</a>, with the extracellular domain of IFNAR2 being the ligand. The fraction amplitude (Amp) of antiviral response (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.g002\" target=\"_blank\">Fig 2</a>) and the errors (in parenthesis) were calculated from the IFN AV dose-response curves. EC<sub>50</sub> values are calculated from <i>In situ</i> measurements of <sup>125</sup>I labelled IFNs binding to the cell surface. Standard Error for <i>k</i><sub>a</sub> values is 25%, for <i>k</i><sub>d</sub> is 15% and for <i>K</i><sub>D</sub> is 30%.</p><p>Binding constants and antiviral response of wild-type IFNα2 and its mutants.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478364, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.t001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Binding_constants_and_antiviral_response_of_wild_type_IFN_945_2_and_its_mutants_/1478364", "title"=>"Binding constants and antiviral response of wild-type IFNα2 and its mutants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169206"], "description"=>"<p>Obtaining a gene induction signature of the various IFN variants for ~100 interferon induced genes using the fluidigm system. (A) Comparison of the fold change in gene expression of WISH cells treated with 200 nM IFN-1ant versus the other antagonists. The doted line represents a slope of one. (B) Clustering analysis of -ΔC<sub>T</sub> values in the indicated cell lines of gene expression data with the indicated IFNs treatments for 8 hours (left) and 24 hours (right).</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478361, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g006", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_induction_signature_upon_interferon_treatments_/1478361", "title"=>"Gene induction signature upon interferon treatments.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169204"], "description"=>"<p>Gene expression in OVCAR3, WISH and T47D cells in response to antagonists, YNS and IFNα2. (A) Cells were treated for 8 hours with 200 nM antagonists or 1nM YNS, and analyzed by qPCR. The data presented are the relative expression levels compared to those of untreated cells, normalized against HPRT1. (B) As described in (A), but cells were treated for 24 hours. (C) Cells were treated with a combination of 200 nM antagonist and 200 pM IFMα2. Gene induction was analyzed as described in (A). Error bars represent standard deviation of the data.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478359, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g005", "stats"=>{"downloads"=>4, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_expression_in_response_to_antagonist_treatment_/1478359", "title"=>"Gene expression in response to antagonist treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169200"], "description"=>"<p>Cell survival was monitored 72 hours post IFN treatment by crystal violet staining. The fraction cell density is relative to untreated cells, with the line in panels A and B indicating cell survival upon 1nM YNS treatment. (A) OVCAR3 cells, (B) WISH cells. (C) Comparing cell viability as determined by crystal violet versus the colorimetric XTT assay, using 1nM YNS and 10nM IFNα2. (D) Reduction in cell count upon treatment of WISH cells with 2, 20 or 200 nM IFNα2 together with 200 or 500 nM antagonists for 72 hours. The grey line indicates cell survival upon 10 nM IFNα2 treatment. The antiproliferative activity of each IFN alone is presented at the right side of the chart (Control). The error bars are SE from 3 independent experiments.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478355, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiproliferative_activities_of_the_type_1_IFN_antagonists_/1478355", "title"=>"Antiproliferative activities of the type 1 IFN antagonists.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169199"], "description"=>"<p>(A) Ribbon representation (based on Protein Data Bank #3SE3) [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.ref029\" target=\"_blank\">29</a>] of the ternary complex of IFNAR1 (R1), IFNAR2 (R2) and IFN, including the locations of the point mutations of the antagonists. On the right is a representation of the antagonist, which binds tighter to R2, but does not bind R1. (B) SPR sensograms of different IFNs (analyte) binding IFNAR2 (surface bound ligand) measured on a ProteOnXPR36. (C) IFNAR1-binding equilibrium analysis of the antagonists and IFNα2. The measurements were done using the ProteOn XPR36 Protein Interaction Array System (BioRad) with IFNAR1 and IFNAR2 immobilized on the sensor chip. For equilibrium binding analysis towards IFNAR1, six different concentrations of the interferon proteins were administrated, and the data were fitted using the mass action equation. (D) <i>In situ</i> measurements of the interferon antagonists towards the IFNAR receptor subunits. The 50% competition values for the four antagonists are ~1 nM, in line with their binding affinities to IFNAR2. 1000-fold lower than the EC<sub>50</sub> value determined for YNS. All extracted data from panels C-E are presented in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130797#pone.0130797.t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["Type 1 Interferon Antagonist Type", "Fine Tuning", "agonistic activity", "aids", "IFNAR 2.", "activity profiles", "Stat phosphorylation", "gene transcription", "interferon antagonists", "IFNAR 1 receptor", "posses immunomudolatory functions", "antiproliferative activity", "gene induction"], "article_id"=>1478354, "categories"=>["Biological Sciences"], "users"=>["Victoria Urin", "Doron Levin", "Nanaocha Sharma", "Daniel Harari", "Gideon Schreiber"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0130797.g001", "stats"=>{"downloads"=>2, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Binding_of_IFN_945_2_and_its_mutants_to_the_IFNAR1_and_IFNAR2_receptor_subunits_/1478354", "title"=>"Binding of IFNα2 and its mutants to the IFNAR1 and IFNAR2 receptor subunits.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:06:56"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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