Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts

Autoři: Gebremedhin Gebremicael aff001;  Desta Kassa aff001;  Yodit Alemayehu aff001;  Atsbeha Gebreegziaxier aff001;  Yonas Kassahun aff003;  Debbie van Baarle aff004;  Tom H. M. Ottenhoff aff005;  Jacqueline M. Cliff aff002;  Mariëlle C. Haks aff005
Působiště autorů: HIV and TB Diseases Research Directorate, Ethiopian Public Health Institute (EPHI), Addis Ababa, Ethiopia aff001;  TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, England, United Kingdom aff002;  Armauer Hansen Research Institute, Addis Ababa, Ethiopia aff003;  Center for Immunology of Infectious Diseases and Vaccins (IIV), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands aff004;  Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226137



Validation of previously identified candidate biomarkers and identification of additional candidate gene expression profiles to facilitate diagnosis of tuberculosis (TB) disease and monitoring treatment responses in the Ethiopian context is vital for improving TB control in the future.


Expression levels of 105 immune-related genes were determined in the blood of 80 HIV-negative study participants composed of 40 active TB cases, 20 latent TB infected individuals with positive tuberculin skin test (TST+), and 20 healthy controls with no Mycobacterium tuberculosis (Mtb) infection (TST-), using focused gene expression profiling by dual-color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification assay. Gene expression levels were also measured six months after anti-TB treatment (ATT) and follow-up in 38 TB patients.


The expression of 15 host genes in TB patients could accurately discriminate between TB cases versus both TST+ and TST- controls at baseline and thus holds promise as biomarker signature to classify active TB disease versus latent TB infection in an Ethiopian setting. Interestingly, the expression levels of most genes that markedly discriminated between TB cases versus TST+ or TST- controls did not normalize following completion of ATT therapy at 6 months (except for PTPRCv1, FCGR1A, GZMB, CASP8 and GNLY) but had only fully normalized at the 18 months follow-up time point. Of note, network analysis comparing TB-associated host genes identified in the current HIV-negative TB cohort to TB-associated genes identified in our previously published Ethiopian HIV-positive TB cohort, revealed an over-representation of pattern recognition receptors including TLR2 and TLR4 in the HIV-positive cohort which was not seen in the HIV-negative cohort. Moreover, using ROC cutoff ≥ 0.80, FCGR1A was the only marker with classifying potential between TB infection and TB disease regardless of HIV status.


Our data indicate that complex gene expression signatures are required to measure blood transcriptomic responses during and after successful ATT to fully diagnose TB disease and characterise drug-induced relapse-free cure, combining genes which resolve completely during the 6-months treatment phase of therapy with genes that only fully return to normal levels during the post-treatment resolution phase.

Klíčová slova:

Blood – Gene expression – Immune response – Pattern recognition receptors – T cells – Tuberculosis – Tuberculosis diagnosis and management


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2019 Číslo 12