Functional Correlations of Pathogenesis-Driven Gene Expression Signatures in Tuberculosis

Abstract

Tuberculosis remains a major health threat and its control depends on improved measures of prevention, diagnosis and treatment. Biosignatures can play a significant role in the development of novel intervention measures against TB and blood transcriptional profiling is increasingly exploited for their rational design. Such profiles also reveal fundamental biological mechanisms associated with the pathology of the disease. We have compared whole blood gene expression in TB patients, as well as in healthy infected and uninfected individuals in a cohort in The Gambia, West Africa and validated previously identified signatures showing high similarities of expression profiles among different cohorts. In this study, we applied a unique combination of classical gene expression analysis with pathway and functional association analysis integrated with intra-individual expression correlations. These analyses were employed for identification of new disease-associated gene signatures, identifying a network of Fc gamma receptor 1 signaling with correlating transcriptional activity as hallmark of gene expression in TB. Remarkable similarities to characteristic signatures in the autoimmune disease systemic lupus erythematosus (SLE) were observed. Functional gene clusters of immunoregulatory interactions involving the JAK-STAT pathway; sensing of microbial patterns by Toll-like receptors and IFN-signaling provide detailed insights into the dysregulation of critical immune processes in TB, involving active expression of both pro-inflammatory and immunoregulatory systems. We conclude that transcriptomics (i) provides a robust system for identification and validation of biosignatures for TB and (ii) application of integrated analysis tools yields novel insights into functional networks underlying TB pathogenesis.

Common patterns and disease-related signatures in tuberculosis and sarcoidosis

“…The genes in this Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (KEGG ID hsa05152; i.e., genes with established significant relation to TB) revealed highly similar differential expression patterns in both diseases compared with healthy individuals. The same was observed for genes involved in several other KEGG pathways that were previously shown to include a significant number of genes that are differentially regulated in TB compared with healthy individuals (6). These pathways include genes in systemic lupus erythematosus, complement and coagulation cascades, toll-like receptor signaling, and Fc γ-receptor-mediated phagocytosis ( Table 2).…”

“…G ene expression in peripheral blood cells from tuberculosis (TB) patients and healthy controls, both latently Mycobacterium tuberculosis-infected and uninfected, has been profiled by several groups in the recent past (1)(2)(3)(4)(5)(6)(7). Identified expression profiles indicate chronic activation of the immune system, with a marked activation of IFN signaling (3), proinflammatory signaling through the JAK-STAT pathway (5,6), and elevated expression of Fc γ-receptors and their downstream response elements (2,4).…”

“…Identified expression profiles indicate chronic activation of the immune system, with a marked activation of IFN signaling (3), proinflammatory signaling through the JAK-STAT pathway (5,6), and elevated expression of Fc γ-receptors and their downstream response elements (2,4). Although these biosignatures have been identified by several independent groups and possess the potential to discriminate latently M. tuberculosis-infected healthy individuals from active TB patients, the question remains whether these gene expression signatures are specific for TB or shared, at least in part, with diseases of similar pathology but distinct etiology.…”

Quest for Correlates of Protection against Tuberculosis

“…TB disease itself is associated with an inflammatory transcriptional blood signature absent in healthy or most latently infected individuals (95)(96)(97)(98)(99)(100)(101). There are several challenging issues in identifying the true correlates of protection against TB, including the lack of good human challenge models and lack of characterization of immune protective cells for ex vivo measurements.…”

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…These studies mostly relied on peripheral blood samples from patients with active ( pulmonary) TB disease directly after diagnosis and contrasted gene expression profiles to those of healthy (infected) controls or patients with other inflammatory/pulmonary disorders (Jacobsen et al 2007;Mistry et al 2007;Berry et al 2010;Maertzdorf et al 2011aMaertzdorf et al ,b, 2012Bloom et al 2013;Cliff et al 2013;Kaforou et al 2013). Each individual study performed extensive data analysis to identify key signatures that could discriminate TB disease from the respective control group(s).…”