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Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function
Cheryl Hemingway1, Maurice Berk2, Suzanne T Anderson1
1Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, Norfolk Place, London, United Kingdom.
Insights
Childhood tuberculosis (TB) involves decreased immune gene expression, impairing T-cell responses. This acquired immune defect may hinder pathogen containment, suggesting new treatment avenues.
Area of Science:
- Immunology
- Genomics
- Pediatrics
Background:
- Tuberculosis (TB) affects millions of children globally, with significant mortality from extrapulmonary disease.
- Current understanding of immune responses in childhood TB, particularly TB meningitis (TBM), is limited.
- Skin test anergy in TB suggests immune system failure, necessitating deeper investigation into immune mechanisms.
Purpose of the Study:
- To investigate genome-wide gene expression in children with TBM to understand immune mechanisms.
- To validate findings in cohorts with pulmonary TB (PTB) and other extrapulmonary TB (EPTB).
- To assess functional T-cell responses in relation to observed gene expression patterns.
Main Methods:
- Genome-wide whole blood RNA expression analysis in children with TBM.
- Validation of gene expression findings in independent cohorts of TBM and PTB patients.
- Functional T-cell proliferation assays in children with various forms of TB.
Main Results:
- Predominant finding in TBM was decreased abundance of multiple immune-related genes (68% of differentially regulated genes).
- Gene expression patterns were validated in PTB patients, though with a lesser magnitude of change.
- Reduced gene expression correlated with impaired T-cell proliferation, which improved after treatment.
Conclusions:
- Childhood TB, especially TBM, is associated with decreased expression of genes involved in immune cell activation.
- An acquired immune defect may contribute to the inability to contain TB infection in children.
- Understanding the mechanisms of this immune paresis could lead to novel therapeutic and preventive strategies.
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.
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