CD14 and Complement Crosstalk and Largely Mediate the Transcriptional Response to Escherichia coli in Human Whole Blood as Revealed by DNA Microarray
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{"title"=>"CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray", "type"=>"journal", "authors"=>[{"first_name"=>"Corinna", "last_name"=>"Lau", "scopus_author_id"=>"52463922600"}, {"first_name"=>"Ståle", "last_name"=>"Nygård", "scopus_author_id"=>"21734889500"}, {"first_name"=>"Hilde", "last_name"=>"Fure", "scopus_author_id"=>"6603274516"}, {"first_name"=>"Ole Kristoffer", "last_name"=>"Olstad", "scopus_author_id"=>"6701841882"}, {"first_name"=>"Marit", "last_name"=>"Holden", "scopus_author_id"=>"7102163440"}, {"first_name"=>"Knut Tore", "last_name"=>"Lappegård", "scopus_author_id"=>"6701379992"}, {"first_name"=>"Ole Lars", "last_name"=>"Brekke", "scopus_author_id"=>"7003310340"}, {"first_name"=>"Terje", "last_name"=>"Espevik", "scopus_author_id"=>"7005312470"}, {"first_name"=>"Eivind", "last_name"=>"Hovig", "scopus_author_id"=>"7004194119"}, {"first_name"=>"Tom Eirik", "last_name"=>"Mollnes", "scopus_author_id"=>"35597368000"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84923792613", "pmid"=>"25706641", "sgr"=>"84923792613", "doi"=>"10.1371/journal.pone.0117261", "issn"=>"19326203", "pui"=>"602523591"}, "id"=>"eb8d31ab-5f34-3add-bf80-a684641bb031", "abstract"=>"Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.", "link"=>"http://www.mendeley.com/research/cd14-complement-crosstalk-largely-mediate-transcriptional-response-escherichia-coli-human-whole-bloo", "reader_count"=>5, "reader_count_by_academic_status"=>{"Researcher"=>3, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>3, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Mathematics"=>1, "Medicine and Dentistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Mathematics"=>{"Mathematics"=>1}}, "reader_count_by_country"=>{"Norway"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1920430"], "description"=>"<p>Crosstalk between CD14 and C3 was assumed when the sum of single inhibitory effects was significantly different from the inhibitory effect of combined inhibition in ANOVA-based interaction effect analyses. This scenario was found for 251 <i>ERG</i>s, designated IAEs. A, The Venn diagram shows the distribution of <i>ERG</i>s with significant effects (ANOVA-based analysis) of single CD14 or C3 inhibition among the 251 IAE genes. Common genes are encompassed by more than one circle. The total numbers for IAEs with significant effects of C3- or CD14-inhibition were 223 and 125, respectively. IAE genes with both single and combined inhibitory effects (n = 110) were designated IAE-I. Numbers of IAEs without single inhibitory effects are indicated at the bottom right of the diagram (n = 13). B, The graph displays the distribution of IAE-I genes among six classes of crosstalk between CD14 and C3 including synergy, four types of counteraction and redundancy. The different crosstalk types were defined according to individual profiles of reversion and augmentation of the <i>E</i>. <i>coli</i> response upon single and combined inhibition using Limma-derived expression data. C, Hierarchical cluster analysis was based on Limma-derived log<sub>2</sub>FC expression values for the <i>E</i>. <i>coli</i> response of the 251 IAE genes in the absence (<i>E</i>. <i>coli</i>) and presence of the inhibitors of C3, CD14 or both. Each line contains the fold change (FC) expression data (log<sub>2</sub>FC) for a single <i>ERG</i>. Genes with similar responses are clustered according to the hierarchy indicated to the left. Manual examination of the heat map revealed six main clusters of related either down- (clusters 1 and 2) or up-regulated <i>ERG</i>s (clusters 3 to 6). The color key and histogram panel indicate total numbers of transcripts contained by the whole gene expression dataset as a function of their log<sub>2</sub>FC expression values. Negative values are displayed in blue, positive values are displayed in red.</p>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1315117, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0117261.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crosstalk_between_CD14_and_C3_dependent_responses_/1315117", "title"=>"Crosstalk between CD14- and C3-dependent responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-23 02:53:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1930181"], "description"=>"<p><sup>A</sup> According to DAVID Bioinformatics Resources 6.7 (<a href=\"http://david.abcc.ncifcrf.gov:8080/\" target=\"_blank\">http://david.abcc.ncifcrf.gov:8080/</a>)</p><p><sup>B</sup> n, number of genes</p><p><sup>C</sup> C3- and CD14-dependent genes (sensitive to combined inhibition of C3 and CD14)</p><p><sup>D</sup> CD14-dependent genes (sensitive to inhibition of CD14 with anti-CD14)</p><p><sup>E</sup> C3-dependent genes (sensitive to inhibition of C3 with compstatin); see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117261#pone.0117261.s017\" target=\"_blank\">S7 Table</a> for gene annotation enrichment analysis of specific subsets of C3- and/or C5a receptor-dependent genes</p><p>Gene annotation enrichment analysis of specific subsets of C3- and/or CD14-dependent <i>ERGs</i> (DAVID<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117261#t003fn001\" target=\"_blank\"><sup>A</sup></a>; <i>p</i><0.05).</p>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1322380, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0117261.t003", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_annotation_enrichment_analysis_of_specific_subsets_of_C3_and_or_CD14_dependent_ERGs_DAVID_A_p_/1322380", "title"=>"Gene annotation enrichment analysis of specific subsets of C3- and/or CD14-dependent <i>ERGs</i> (DAVID<sup>A</sup>; <i>p</i><0.05).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-02-23 16:39:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/1930182"], "description"=>"<p><sup>A</sup> Genes with fold change (FC) expression in response to <i>E</i>. <i>coli</i> above two-fold (FC > 2; bold) listed, only, except for P2RX7; see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117261#pone.0117261.s004\" target=\"_blank\">S4 Fig</a>. for detailed illustration of the pathway</p><p><sup>B</sup><i>n</i>.<i>s</i>., not significant with FDR <i>q</i>-value > 0.05 (Limma) or <i>p</i>>0.05 (ANOVA; IAE cluster)</p><p><sup>C</sup> P2RX7: FC > 2 in C5-deficient patient; see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117261#pone.0117261.s021\" target=\"_blank\">S11 Table</a> for data from a C5-deficient patient.</p><p>Expression parameters of <i>ERG</i>s of the IPA canonical pathway <i>Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses</i>.</p>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1322381, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0117261.t004", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_parameters_of_ERG_s_of_the_IPA_canonical_pathway_Role_of_Pattern_Recognition_Receptors_in_Recognition_of_Bacteria_and_Viruses_/1322381", "title"=>"Expression parameters of <i>ERG</i>s of the IPA canonical pathway <i>Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses</i>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-02-23 16:39:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/1930183", "https://ndownloader.figshare.com/files/1930184", "https://ndownloader.figshare.com/files/1930185", "https://ndownloader.figshare.com/files/1930186", "https://ndownloader.figshare.com/files/1930187", "https://ndownloader.figshare.com/files/1930188", "https://ndownloader.figshare.com/files/1930189", "https://ndownloader.figshare.com/files/1930190", "https://ndownloader.figshare.com/files/1930191", "https://ndownloader.figshare.com/files/1930192", "https://ndownloader.figshare.com/files/1930193", "https://ndownloader.figshare.com/files/1930194", "https://ndownloader.figshare.com/files/1930195", "https://ndownloader.figshare.com/files/1930196", "https://ndownloader.figshare.com/files/1930197", "https://ndownloader.figshare.com/files/1930198", "https://ndownloader.figshare.com/files/1930199", "https://ndownloader.figshare.com/files/1930200", "https://ndownloader.figshare.com/files/1930201", "https://ndownloader.figshare.com/files/1930202", "https://ndownloader.figshare.com/files/1930203"], "description"=>"<div><p>Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated <i>Escherichia coli</i> by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the <i>Escherichia coli</i>-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.</p></div>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1322382, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0117261.s001", "https://dx.doi.org/10.1371/journal.pone.0117261.s002", "https://dx.doi.org/10.1371/journal.pone.0117261.s003", "https://dx.doi.org/10.1371/journal.pone.0117261.s004", "https://dx.doi.org/10.1371/journal.pone.0117261.s005", "https://dx.doi.org/10.1371/journal.pone.0117261.s006", "https://dx.doi.org/10.1371/journal.pone.0117261.s007", "https://dx.doi.org/10.1371/journal.pone.0117261.s008", "https://dx.doi.org/10.1371/journal.pone.0117261.s009", "https://dx.doi.org/10.1371/journal.pone.0117261.s010", "https://dx.doi.org/10.1371/journal.pone.0117261.s011", "https://dx.doi.org/10.1371/journal.pone.0117261.s012", "https://dx.doi.org/10.1371/journal.pone.0117261.s013", "https://dx.doi.org/10.1371/journal.pone.0117261.s014", "https://dx.doi.org/10.1371/journal.pone.0117261.s015", "https://dx.doi.org/10.1371/journal.pone.0117261.s016", "https://dx.doi.org/10.1371/journal.pone.0117261.s017", "https://dx.doi.org/10.1371/journal.pone.0117261.s018", "https://dx.doi.org/10.1371/journal.pone.0117261.s019", "https://dx.doi.org/10.1371/journal.pone.0117261.s020", "https://dx.doi.org/10.1371/journal.pone.0117261.s021"], "stats"=>{"downloads"=>49, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CD14_and_Complement_Crosstalk_and_Largely_Mediate_the_Transcriptional_Response_to_Escherichia_coli_in_Human_Whole_Blood_as_Revealed_by_DNA_Microarray/1322382", "title"=>"CD14 and Complement Crosstalk and Largely Mediate the Transcriptional Response to <i>Escherichia coli</i> in Human Whole Blood as Revealed by DNA Microarray", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-02-23 16:39:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/1920428"], "description"=>"<p>A, The diagram shows common and specific groups of reversible C3-dependent genes (C3-DGs), CD14-DGs and C3/CD14-DGs DGs. Common genes are encompassed by more than one circle. The sum of all numbers within the diagrams equals the total number of <i>ERG</i>s (n = 2335). Numbers of <i>ERG</i>s which belong to none of the respective DG groups are indicated at the bottom right of the diagram. B and C, The remaining <i>E</i>. <i>coli</i>-induced transcriptional responses of reversible <i>ERG</i>s (in % of total) in the presence of inhibitors were derived from the transcriptional response in the presence of inhibitors of C3 (n = 334), CD14 (n = 1323) or both (combined inhibition; n = 1626) divided by the uninhibited response (set to 100%). Data are shown for up- and down-regulated <i>ERG</i>s (B), and for <i>ERG</i>s with fold change (FC) responses above (FC<2) or below two-fold (FC<2) (C). Data are given as mean and SEM. The significances of the differences between combined inhibitory effect and single inhibitory effects were determined by Two-way ANOVA and Bonferroni post-testing (***, <i>p</i><0.001). D and E, The Venn diagrams show augmentable C3-DGs, CD14-DGs and C3/CD14-DGs (D) or augmentable C3-DGs (gray circles) compared to reversible CD14-DGs and C3/CD14-DGs (white circles) (E). The total numbers of DGs are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117261#pone.0117261.t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1315115, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0117261.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD14_and_or_C3_inhibition_of_the_transcriptional_response_to_E_coli_/1315115", "title"=>"CD14 and/or C3 inhibition of the transcriptional response to <i>E</i>. <i>coli</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-23 02:53:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1920429"], "description"=>"<p>Relative quantification (RQ) data from qPCR analyses are displayed as scatter plots for the <i>E</i>. <i>coli</i> response of seven <i>ERG</i>s and non-responding TLR4 in absence (A) and presence (B) of combined inhibition of C3 and CD14. Data are shown for two sets of data, the controls included in the microarray study (●; single data points, n = 2) and five independent individuals (○; single data points, n = 5 with mean). The expression data were normalized to spontaneous activation in presence of PBS, only, which is indicated as a dotted line crossing the Y-axis (log<sub>2</sub> scale) at RQ = 1. No statistical significance of the differences between the two datasets was found for the uninhibited (P = 0.82) and the inhibited response (P = 0.89) in a two-tailed unpaired t-test with Welch’s correction.</p>", "links"=>[], "tags"=>["inhibition", "escherichia", "complement", "response", "gene annotation analyses", "tlr", "dna", "CD 14 dependency", "transcriptional", "C 3", "CD 14"], "article_id"=>1315116, "categories"=>["Biological Sciences"], "users"=>["Corinna Lau", "Ståle Nygård", "Hilde Fure", "Ole Kristoffer Olstad", "Marit Holden", "Knut Tore Lappegård", "Ole-Lars Brekke", "Terje Espevik", "Eivind Hovig", "Tom Eirik Mollnes"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0117261.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inter_individual_variations_of_the_E_coli_response_of_selected_genes_/1315116", "title"=>"Inter-individual variations of the <i>E</i>. <i>coli</i> response of selected genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-23 02:53:00"}

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  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"21", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"21", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"17", "full-text"=>"17", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}

Relative Metric

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