The Transcriptional Signature of Active Tuberculosis Reflects Symptom Status in Extra-Pulmonary and Pulmonary Tuberculosis.

Simon Blankley,Zhaohui Xu,Anne O’Garra,Ronan Breen,Jacques Banchereau,Matthew P R Berry,Christine M Graham,Marc Lipman,Chloe I Bloom,Virginia Pascual,Jacob Turner,Derek M Blankenship,George Santis,Damien Chaussabel

doi:10.1371/journal.pone.0162220

Abstract

BackgroundMycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis.MethodsA novel cohort of patients with extra-pulmonary TB and sarcoidosis was recruited and the transcriptional response of these patients compared to those with pulmonary TB using a variety of transcriptomic approaches including testing a previously defined 380 gene meta-signature of active TB.ResultsThe 380 meta-signature broadly differentiated active TB from healthy controls in this new dataset consisting of pulmonary and extra-pulmonary TB. The top 15 genes from this meta-signature had a lower sensitivity for differentiating extra-pulmonary TB from healthy controls as compared to pulmonary TB. We found the blood transcriptional responses in pulmonary and extra-pulmonary TB to be heterogeneous and to reflect the extent of symptoms of disease.ConclusionsThe transcriptional signature in extra-pulmonary TB demonstrated heterogeneity of gene expression reflective of symptom status, while the signature of pulmonary TB was distinct, based on a higher proportion of symptomatic individuals. These findings are of importance for the rational design and implementation of mRNA based TB diagnostics.

Highlights

Mycobacterium tuberculosis (Mtb) continues to be a significant cause of mortality and morbidity worldwide [1]
An interferon-dominated 393 transcript signature was identified from human whole blood which was present in active TB and absent in the majority of healthy and latently infected individuals and was shown to correlate with the extent of radiographic lung disease [6]
There was no difference in gender frequency (Fig 1A) between groups there were differences in the group composition with regard to ethnicity and age, with the sarcoidosis group being significantly older than the other groups and tending to have less patients of Indian subcontinent background (Fig 1B and 1C)

Summary

Introduction

Mycobacterium tuberculosis (Mtb) continues to be a significant cause of mortality and morbidity worldwide [1]. An interferon-dominated 393 transcript signature was identified from human whole blood which was present in active TB and absent in the majority of healthy and latently infected individuals and was shown to correlate with the extent of radiographic lung disease [6]. This finding of enrichment for interferon signalling has since been reported in multiple subsequent studies [7,8,9,10,11]. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis

Methods

Results

Conclusion