Distinct Phases of Blood Gene Expression Pattern Through Tuberculosis Treatment Reflect Modulation of the Humoral Immune Response

Abstract

The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.

A 380-gene meta-signature of active tuberculosis compared with healthy controls

“…We identified remarkable similarity between the datasets, with overexpression of modules annotated with IFN, inflammation functions, monocyte and neutrophil functions, and underexpression of B-and T-cell modules. These findings are in keeping with the individual studies that have included grouped modular analysis [4,7]. Where grouped modular profiles were less consistent, this may have resulted from the small cohort sizes used and emphasises the need for individual studies to be appropriately powered to detect all differentially expressed genes.…”

“…Publicly available datasets that had active TB patients versus healthy controls, latently infected or patients post-treatment were identified and retained. The latter three cohorts are synonymous transcriptionally at the group level [4,6,7]. HIV-infected individuals were excluded from this analysis.…”

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).…”

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

“…The blood gene signature from the publically available data set in the NCBI-GEO (National Center for Biotechnology Information Gene Expression Omnibus) database, accession number GSE31348, was used to analyze PKC expression of all isoforms during TB treatment. 20 For human lung proteomics, we analyzed the available data that have been deposited into the PRIDE partner repository with the data set identifier PXD003646. The heat map plot was constructed by calculating z-scores of PKCd abundance in different types of granulomas derived from multidrug-resistant TB patients.…”

“…We analyzed a publicly available data set from an independent study 20 that reported whole-blood expression profiles of 27 first-time TB patients before and after treatment. We found that PKCd was the most abundantly expressed isoform compared with other PKC isoforms.…”