Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function
The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To...
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creator | Hemingway, Cheryl Berk, Maurice Anderson, Suzanne T Wright, Victoria J Hamilton, Shea Eleftherohorinou, Hariklia Kaforou, Myrsini Goldgof, Greg M Hickman, Katy Kampmann, Beate Schoeman, Johan Eley, Brian Beatty, David Pienaar, Sandra Nicol, Mark P Griffiths, Michael J Waddell, Simon J Newton, Sandra M Coin, Lachlan J Relman, David A Montana, Giovanni Levin, Michael |
description | The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p |
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The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0185973</identifier><identifier>PMID: 29140996</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abundance ; Adolescent ; Anergy ; Antigen presentation ; Biology and Life Sciences ; Case-Control Studies ; Cell activation ; Cell proliferation ; Child ; Child, Preschool ; Childhood ; Children ; Cohort Studies ; Cytokines - genetics ; Epidemiology ; Female ; Gene expression ; Gene Expression Profiling ; Genes ; Genetic aspects ; Genetic engineering ; Genomes ; Hospitals ; Humans ; Immune system ; Immunology ; Infections ; Infectious diseases ; Leukocytes ; Lungs ; Lymphocytes ; Lymphocytes T ; Male ; Medicine ; Medicine and Health Sciences ; Meningitis ; Mycobacterium tuberculosis ; Paresis ; Patients ; People and Places ; Physiological aspects ; Public health ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleic acid ; RNA ; RNA, Messenger - blood ; Signaling ; Skin tests ; T cell receptors ; T cells ; T-cell receptor ; T-Lymphocytes - metabolism ; Transcription activation ; Tuberculosis ; Tuberculosis - genetics ; Tuberculosis - immunology</subject><ispartof>PloS one, 2017-11, Vol.12 (11), p.e0185973-e0185973</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Hemingway 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>2017 Hemingway et al 2017 Hemingway et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-f1be9cac095852fa1e14f3822e0b456b8bc40fd5571cb0832a43b1cedee7c3103</citedby><cites>FETCH-LOGICAL-c692t-f1be9cac095852fa1e14f3822e0b456b8bc40fd5571cb0832a43b1cedee7c3103</cites><orcidid>0000-0001-6545-9558 ; 0000-0002-5797-1188 ; 0000-0001-7826-1516 ; 0000-0002-3480-6497 ; 0000-0002-2329-5599 ; 0000-0003-1213-7787</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/PMC5687722/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687722/$$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/29140996$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Rottenberg, Martin E.</contributor><creatorcontrib>Hemingway, Cheryl</creatorcontrib><creatorcontrib>Berk, Maurice</creatorcontrib><creatorcontrib>Anderson, Suzanne T</creatorcontrib><creatorcontrib>Wright, Victoria J</creatorcontrib><creatorcontrib>Hamilton, Shea</creatorcontrib><creatorcontrib>Eleftherohorinou, Hariklia</creatorcontrib><creatorcontrib>Kaforou, Myrsini</creatorcontrib><creatorcontrib>Goldgof, Greg M</creatorcontrib><creatorcontrib>Hickman, Katy</creatorcontrib><creatorcontrib>Kampmann, Beate</creatorcontrib><creatorcontrib>Schoeman, Johan</creatorcontrib><creatorcontrib>Eley, Brian</creatorcontrib><creatorcontrib>Beatty, David</creatorcontrib><creatorcontrib>Pienaar, Sandra</creatorcontrib><creatorcontrib>Nicol, Mark P</creatorcontrib><creatorcontrib>Griffiths, Michael J</creatorcontrib><creatorcontrib>Waddell, Simon J</creatorcontrib><creatorcontrib>Newton, Sandra M</creatorcontrib><creatorcontrib>Coin, Lachlan J</creatorcontrib><creatorcontrib>Relman, David A</creatorcontrib><creatorcontrib>Montana, Giovanni</creatorcontrib><creatorcontrib>Levin, Michael</creatorcontrib><title>Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.</description><subject>Abundance</subject><subject>Adolescent</subject><subject>Anergy</subject><subject>Antigen presentation</subject><subject>Biology and Life Sciences</subject><subject>Case-Control Studies</subject><subject>Cell activation</subject><subject>Cell proliferation</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Childhood</subject><subject>Children</subject><subject>Cohort Studies</subject><subject>Cytokines - genetics</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Genomes</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunology</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Leukocytes</subject><subject>Lungs</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Meningitis</subject><subject>Mycobacterium tuberculosis</subject><subject>Paresis</subject><subject>Patients</subject><subject>People and Places</subject><subject>Physiological aspects</subject><subject>Public health</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - blood</subject><subject>Signaling</subject><subject>Skin tests</subject><subject>T cell receptors</subject><subject>T cells</subject><subject>T-cell receptor</subject><subject>T-Lymphocytes - metabolism</subject><subject>Transcription 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tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function</title><author>Hemingway, Cheryl ; Berk, Maurice ; Anderson, Suzanne T ; Wright, Victoria J ; Hamilton, Shea ; Eleftherohorinou, Hariklia ; Kaforou, Myrsini ; Goldgof, Greg M ; Hickman, Katy ; Kampmann, Beate ; Schoeman, Johan ; Eley, Brian ; Beatty, David ; Pienaar, Sandra ; Nicol, Mark P ; Griffiths, Michael J ; Waddell, Simon J ; Newton, Sandra M ; Coin, Lachlan J ; Relman, David A ; Montana, Giovanni ; Levin, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f1be9cac095852fa1e14f3822e0b456b8bc40fd5571cb0832a43b1cedee7c3103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Abundance</topic><topic>Adolescent</topic><topic>Anergy</topic><topic>Antigen presentation</topic><topic>Biology and Life Sciences</topic><topic>Case-Control 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Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hemingway, Cheryl</au><au>Berk, Maurice</au><au>Anderson, Suzanne T</au><au>Wright, Victoria J</au><au>Hamilton, Shea</au><au>Eleftherohorinou, Hariklia</au><au>Kaforou, Myrsini</au><au>Goldgof, Greg M</au><au>Hickman, Katy</au><au>Kampmann, Beate</au><au>Schoeman, Johan</au><au>Eley, Brian</au><au>Beatty, David</au><au>Pienaar, Sandra</au><au>Nicol, Mark P</au><au>Griffiths, Michael J</au><au>Waddell, Simon J</au><au>Newton, Sandra M</au><au>Coin, Lachlan J</au><au>Relman, David A</au><au>Montana, Giovanni</au><au>Levin, Michael</au><au>Rottenberg, Martin E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-11-15</date><risdate>2017</risdate><volume>12</volume><issue>11</issue><spage>e0185973</spage><epage>e0185973</epage><pages>e0185973-e0185973</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29140996</pmid><doi>10.1371/journal.pone.0185973</doi><tpages>e0185973</tpages><orcidid>https://orcid.org/0000-0001-6545-9558</orcidid><orcidid>https://orcid.org/0000-0002-5797-1188</orcidid><orcidid>https://orcid.org/0000-0001-7826-1516</orcidid><orcidid>https://orcid.org/0000-0002-3480-6497</orcidid><orcidid>https://orcid.org/0000-0002-2329-5599</orcidid><orcidid>https://orcid.org/0000-0003-1213-7787</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2017-11, Vol.12 (11), p.e0185973-e0185973 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1964557192 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Abundance Adolescent Anergy Antigen presentation Biology and Life Sciences Case-Control Studies Cell activation Cell proliferation Child Child, Preschool Childhood Children Cohort Studies Cytokines - genetics Epidemiology Female Gene expression Gene Expression Profiling Genes Genetic aspects Genetic engineering Genomes Hospitals Humans Immune system Immunology Infections Infectious diseases Leukocytes Lungs Lymphocytes Lymphocytes T Male Medicine Medicine and Health Sciences Meningitis Mycobacterium tuberculosis Paresis Patients People and Places Physiological aspects Public health Reverse Transcriptase Polymerase Chain Reaction Ribonucleic acid RNA RNA, Messenger - blood Signaling Skin tests T cell receptors T cells T-cell receptor T-Lymphocytes - metabolism Transcription activation Tuberculosis Tuberculosis - genetics Tuberculosis - immunology |
title | Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function |
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