The immunosuppressive face of sepsis early on intensive care unit-A large-scale microarray meta-analysis
Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts' immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to furth...
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description | Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts' immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it.
A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent-but in its extent varying-presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics. |
doi_str_mv | 10.1371/journal.pone.0198555 |
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A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent-but in its extent varying-presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0198555</identifier><identifier>PMID: 29920518</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anesthesiology ; Antibiotics ; Antigens, CD - biosynthesis ; Antigens, CD - genetics ; Bioinformatics ; Biology and Life Sciences ; Cell activation ; Cluster Analysis ; Clusters ; Cytokines - biosynthesis ; Cytokines - genetics ; DNA microarrays ; Dosage and administration ; Drug therapy ; Filtration ; Gene expression ; Gene Expression Regulation - immunology ; Gene Regulatory Networks - immunology ; Genes ; Granulocytes - immunology ; Granulocytes - metabolism ; Haptoglobins - biosynthesis ; Haptoglobins - genetics ; Heterogeneity ; Humans ; Immune response ; Immune system ; Immunosuppression ; Immunosuppressive agents ; Infections ; Infectious diseases ; Inflammasomes - genetics ; Inflammasomes - immunology ; Inflammation ; Inflammatory response ; Intensive care ; Intensive care units ; Leukocytes (granulocytic) ; Lymphocytes T ; Management ; Medicine and Health Sciences ; Meta-analysis ; Monocytes ; Monocytes - immunology ; Monocytes - metabolism ; Patient outcomes ; Patients ; Repositories ; Research and Analysis Methods ; Sepsis ; Sepsis - genetics ; Sepsis - immunology ; Studies ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - metabolism ; Tissue Array Analysis ; Transcription ; Transcriptome ; Viral infections</subject><ispartof>PloS one, 2018-06, Vol.13 (6), p.e0198555-e0198555</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Schaack et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Schaack et al 2018 Schaack et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-ec116611a7c7151cad98f26ddeae4458e513924cbfed30f7676b55766524ed1e3</citedby><cites>FETCH-LOGICAL-c692t-ec116611a7c7151cad98f26ddeae4458e513924cbfed30f7676b55766524ed1e3</cites><orcidid>0000-0001-8876-7430</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007920/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007920/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29920518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahuja, Sunil K</contributor><creatorcontrib>Schaack, Dominik</creatorcontrib><creatorcontrib>Siegler, Benedikt Hermann</creatorcontrib><creatorcontrib>Tamulyte, Sandra</creatorcontrib><creatorcontrib>Weigand, Markus Alexander</creatorcontrib><creatorcontrib>Uhle, Florian</creatorcontrib><title>The immunosuppressive face of sepsis early on intensive care unit-A large-scale microarray meta-analysis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts' immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it.
A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent-but in its extent varying-presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.</description><subject>Anesthesiology</subject><subject>Antibiotics</subject><subject>Antigens, CD - biosynthesis</subject><subject>Antigens, CD - genetics</subject><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Cell activation</subject><subject>Cluster Analysis</subject><subject>Clusters</subject><subject>Cytokines - biosynthesis</subject><subject>Cytokines - genetics</subject><subject>DNA microarrays</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Filtration</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - immunology</subject><subject>Gene Regulatory Networks - immunology</subject><subject>Genes</subject><subject>Granulocytes - immunology</subject><subject>Granulocytes - metabolism</subject><subject>Haptoglobins - biosynthesis</subject><subject>Haptoglobins - genetics</subject><subject>Heterogeneity</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunosuppression</subject><subject>Immunosuppressive agents</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Inflammasomes - genetics</subject><subject>Inflammasomes - immunology</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>Intensive care</subject><subject>Intensive care units</subject><subject>Leukocytes (granulocytic)</subject><subject>Lymphocytes T</subject><subject>Management</subject><subject>Medicine and Health Sciences</subject><subject>Meta-analysis</subject><subject>Monocytes</subject><subject>Monocytes - immunology</subject><subject>Monocytes - metabolism</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Repositories</subject><subject>Research and Analysis Methods</subject><subject>Sepsis</subject><subject>Sepsis - genetics</subject><subject>Sepsis - immunology</subject><subject>Studies</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - metabolism</subject><subject>Tissue Array Analysis</subject><subject>Transcription</subject><subject>Transcriptome</subject><subject>Viral infections</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9-L1DAQgIso3nn6H4gWBNGHrkmbpO2LsBz-WDg40NPXkE2muznSpJekh_vfm73tHVu5B-lDS_rNl8xMJsteY7TAVY0_XbvRW2EWg7OwQLhtKKVPslPcVmXBSlQ9Pfo-yV6EcI0QrRrGnmcnZduWiOLmNNtebSHXfT9aF8Zh8BCCvoW8ExJy1-UBhqBDDsKbXe5srm0Ee0dI4SEfrY7FMjfCb6AIUhjIey29E96LXd5DFIVIZ9wlx8vsWSdMgFfT-yz79fXL1fn34uLy2-p8eVFI1paxAIkxYxiLWtaYYilU23QlUwoEEEIboLhqSyLXHagKdTWr2ZrSmjFaElAYqrPs7cE7GBf4VKTAU7o1oin7KhGrA6GcuOaD173wO-6E5ncLzm-48FFLA5zUTFFGGigpJQyxNaFkXdfAGqWQqnByfZ52G9c9KAk2emFm0vkfq7d84245Q6hOPUiCD5PAu5sRQuS9DhKMERbceDg3IRUle_TdP-jj2U3UJnWDa9u5tK_cS_mSJhGlLd27Fo9Q6VGQGphuVKfT-izg4ywgMRH-xI0YQ-Crnz_-n738PWffH7FbECZugzNj1M6GOUgOYLpeIXjoHoqMEd8PxH01-H4g-DQQKezNcYMegu4noPoLerIFvw</recordid><startdate>20180619</startdate><enddate>20180619</enddate><creator>Schaack, Dominik</creator><creator>Siegler, Benedikt Hermann</creator><creator>Tamulyte, Sandra</creator><creator>Weigand, Markus Alexander</creator><creator>Uhle, Florian</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-8876-7430</orcidid></search><sort><creationdate>20180619</creationdate><title>The immunosuppressive face of sepsis early on intensive care unit-A large-scale microarray meta-analysis</title><author>Schaack, Dominik ; Siegler, Benedikt Hermann ; Tamulyte, Sandra ; Weigand, Markus Alexander ; Uhle, Florian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-ec116611a7c7151cad98f26ddeae4458e513924cbfed30f7676b55766524ed1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Anesthesiology</topic><topic>Antibiotics</topic><topic>Antigens, CD - biosynthesis</topic><topic>Antigens, CD - genetics</topic><topic>Bioinformatics</topic><topic>Biology and Life Sciences</topic><topic>Cell activation</topic><topic>Cluster Analysis</topic><topic>Clusters</topic><topic>Cytokines - biosynthesis</topic><topic>Cytokines - genetics</topic><topic>DNA microarrays</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>Filtration</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - immunology</topic><topic>Gene Regulatory Networks - immunology</topic><topic>Genes</topic><topic>Granulocytes - immunology</topic><topic>Granulocytes - metabolism</topic><topic>Haptoglobins - biosynthesis</topic><topic>Haptoglobins - genetics</topic><topic>Heterogeneity</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunosuppression</topic><topic>Immunosuppressive agents</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Inflammasomes - genetics</topic><topic>Inflammasomes - 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Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it.
A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent-but in its extent varying-presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29920518</pmid><doi>10.1371/journal.pone.0198555</doi><tpages>e0198555</tpages><orcidid>https://orcid.org/0000-0001-8876-7430</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Anesthesiology Antibiotics Antigens, CD - biosynthesis Antigens, CD - genetics Bioinformatics Biology and Life Sciences Cell activation Cluster Analysis Clusters Cytokines - biosynthesis Cytokines - genetics DNA microarrays Dosage and administration Drug therapy Filtration Gene expression Gene Expression Regulation - immunology Gene Regulatory Networks - immunology Genes Granulocytes - immunology Granulocytes - metabolism Haptoglobins - biosynthesis Haptoglobins - genetics Heterogeneity Humans Immune response Immune system Immunosuppression Immunosuppressive agents Infections Infectious diseases Inflammasomes - genetics Inflammasomes - immunology Inflammation Inflammatory response Intensive care Intensive care units Leukocytes (granulocytic) Lymphocytes T Management Medicine and Health Sciences Meta-analysis Monocytes Monocytes - immunology Monocytes - metabolism Patient outcomes Patients Repositories Research and Analysis Methods Sepsis Sepsis - genetics Sepsis - immunology Studies T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism Tissue Array Analysis Transcription Transcriptome Viral infections |
title | The immunosuppressive face of sepsis early on intensive care unit-A large-scale microarray meta-analysis |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T06%3A05%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20immunosuppressive%20face%20of%20sepsis%20early%20on%20intensive%20care%20unit-A%20large-scale%20microarray%20meta-analysis&rft.jtitle=PloS%20one&rft.au=Schaack,%20Dominik&rft.date=2018-06-19&rft.volume=13&rft.issue=6&rft.spage=e0198555&rft.epage=e0198555&rft.pages=e0198555-e0198555&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0198555&rft_dat=%3Cgale_plos_%3EA543555950%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2057058663&rft_id=info:pmid/29920518&rft_galeid=A543555950&rft_doaj_id=oai_doaj_org_article_476d5648e2554606b454b77e68dd0d31&rfr_iscdi=true |