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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Main Authors: Cheryl Hemingway, Maurice Berk, Suzanne T Anderson, Victoria J Wright, Shea Hamilton, Hariklia Eleftherohorinou, Myrsini Kaforou, Greg M Goldgof, Katy Hickman, Beate Kampmann, Johan Schoeman, Brian Eley, David Beatty, Sandra Pienaar, Mark P Nicol, Michael J Griffiths, Simon J Waddell, Sandra M Newton, Lachlan J Coin, David A Relman, Giovanni Montana, Michael Levin
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2017-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC5687722?pdf=render
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author Cheryl Hemingway
Maurice Berk
Suzanne T Anderson
Victoria J Wright
Shea Hamilton
Hariklia Eleftherohorinou
Myrsini Kaforou
Greg M Goldgof
Katy Hickman
Beate Kampmann
Johan Schoeman
Brian Eley
David Beatty
Sandra Pienaar
Mark P Nicol
Michael J Griffiths
Simon J Waddell
Sandra M Newton
Lachlan J Coin
David A Relman
Giovanni Montana
Michael Levin
author_facet Cheryl Hemingway
Maurice Berk
Suzanne T Anderson
Victoria J Wright
Shea Hamilton
Hariklia Eleftherohorinou
Myrsini Kaforou
Greg M Goldgof
Katy Hickman
Beate Kampmann
Johan Schoeman
Brian Eley
David Beatty
Sandra Pienaar
Mark P Nicol
Michael J Griffiths
Simon J Waddell
Sandra M Newton
Lachlan J Coin
David A Relman
Giovanni Montana
Michael Levin
author_sort Cheryl Hemingway
collection DOAJ
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.
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spelling doaj.art-98998fabc3a442a9a50a5b8bae6715012022-12-21T23:27:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011211e018597310.1371/journal.pone.0185973Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.Cheryl HemingwayMaurice BerkSuzanne T AndersonVictoria J WrightShea HamiltonHariklia EleftherohorinouMyrsini KaforouGreg M GoldgofKaty HickmanBeate KampmannJohan SchoemanBrian EleyDavid BeattySandra PienaarMark P NicolMichael J GriffithsSimon J WaddellSandra M NewtonLachlan J CoinDavid A RelmanGiovanni MontanaMichael LevinThe 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.http://europepmc.org/articles/PMC5687722?pdf=render
spellingShingle Cheryl Hemingway
Maurice Berk
Suzanne T Anderson
Victoria J Wright
Shea Hamilton
Hariklia Eleftherohorinou
Myrsini Kaforou
Greg M Goldgof
Katy Hickman
Beate Kampmann
Johan Schoeman
Brian Eley
David Beatty
Sandra Pienaar
Mark P Nicol
Michael J Griffiths
Simon J Waddell
Sandra M Newton
Lachlan J Coin
David A Relman
Giovanni Montana
Michael Levin
Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
PLoS ONE
title Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
title_full Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
title_fullStr Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
title_full_unstemmed Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
title_short Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.
title_sort childhood tuberculosis is associated with decreased abundance of t cell gene transcripts and impaired t cell function
url http://europepmc.org/articles/PMC5687722?pdf=render
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