Abstract
BackgroundHumans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. However, the factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from latent infection.Methodology/Principal FindingsUsing microarray analysis, we comprehensively determined the transcriptional difference in purified protein derivative (PPD) stimulated peripheral blood mononuclear cells (PBMCs) in 12 individuals divided into three groups: TB patients (TB), latent TB infection individuals (LTBI) and healthy controls (HC) (n = 4 per group). A transcriptional profiling of 506 differentially expressed genes could correctly group study individuals into three clusters. Moreover, 55- and 229-transcript signatures for tuberculosis infection (TB<BI) and active disease (TB) were identified, respectively. The validation study by quantitative real-time PCR (qPCR) performed in 83 individuals confirmed the expression patterns of 81% of the microarray identified genes. Decision tree analysis indicated that three genes of CXCL10, ATP10A and TLR6 could differentiate TB from LTBI subjects. Additional validation was performed to assess the diagnostic ability of the three biomarkers within 36 subjects, which yielded a sensitivity of 71% and specificity of 89%.Conclusions/SignificanceThe transcription profiles of PBMCs induced by PPD identified distinctive gene expression patterns associated with different infectious status and provided new insights into human immune responses to MTB. Furthermore, this study indicated that a combination of CXCL10, ATP10A and TLR6 could be used as novel biomarkers for the discrimination of TB from LTBI.
Highlights
Tuberculosis remains a leading infectious disease worldwide
The gene ontology (GO) analysis of differentially expressed genes revealed that genes associated with extracellular component and movement in response to external stimulus were significantly enriched in the comparison of latent TB infection individuals (LTBI) and healthy controls (HC)
We described the global gene expression differences in TB, LTBI and HC, and identified distinct transcriptional signatures of tuberculosis infection and active disease
Summary
Tuberculosis remains a leading infectious disease worldwide. There were 9.4 million new TB cases with 1.6 million deaths in 2009 and about 2 billion people were latently infected with MTB [1,2]. Most people infected with MTB remain asymptomatic, termed LTBI, presumably due to human protective immune response [3,4]. Immunological determinants of host-pathogen interactions resulting in disease progression, latency or clearance remain poorly understood. Human immune factors are known to play a pivotal role in the control of infection [8,9,10], more immunological network signatures with respect to disease, MTB infection or clearance need to be defined [11,12]. Humans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. The factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from latent infection
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