Abstract
BackgroundTuberculosis (TB) is a major infectious disease, where incomplete information about host genetics and immune responses is hindering the development of transformative therapies. This study characterized the immune cell landscape and blood transcriptomic profile of patients with pulmonary TB (PTB) to identify the potential therapeutic biomarkers.MethodsThe blood transcriptome profile of patients with PTB and controls were used for fractionating immune cell populations with the CIBERSORT algorithm and then to identify differentially expressed genes (DEGs) with R/Bioconductor packages. Later, systems biology investigations (such as semantic similarity, gene correlation, and graph theory parameters) were implemented to prioritize druggable genes contributing to the immune cell alterations in patients with TB. Finally, real time-PCR (RT-PCR) was used to confirm gene expression levels.ResultsPatients with PTB had higher levels of four immune subpopulations like CD8+ T cells (P = 1.9 × 10−8), natural killer (NK) cells resting (P = 6.3 × 10−5), monocytes (P = 6.4 × 10−6), and neutrophils (P = 1.6 × 10−7). The functional enrichment of 624 DEGs identified in the blood transcriptome of patients with PTB revealed major dysregulation of T cell-related ontologies and pathways (q ≤ 0.05). Of the 96 DEGs shared between transcriptome and immune cell types, 39 overlapped with TB meta-profiling genetic signatures, and their semantic similarity analysis with the remaining 57 genes, yielded 45 new candidate TB markers. This study identified 9 CD8+ T cell-associated genes (ITK, CD2, CD6, CD247, ZAP70, CD3D, SH2D1A, CD3E, and IL7R) as potential therapeutic targets of PTB by combining computational druggability and co-expression (r2 ≥ |0.7|) approaches.ConclusionThe changes in immune cell proportion and the downregulation of T cell-related genes may provide new insights in developing therapeutic compounds against chronic TB.
Highlights
Tuberculosis (TB) is a chronic infectious lung disease caused by pathogenic Mycobacterium tuberculosis (MTB) belonging to the Mycobacteriaceae family
differentially expressed genes (DEGs) associated with 12 innate immune cell type categories were NK cells resting, macrophages M2, monocytes, macrophages M1, macrophages M0, resting dendritic cells, eosinophils, dendritic cells activated, mast cells resting, NK cells activated, mast cells activated, and neutrophils were found be enriched
We observed higher relative proportion of genes enriched for cell types like CD8+ T cells (P = 1.9 × 10−8), NK cells resting (P = 6.3 × 10−5), monocytes (P = 6.4 × 10−6), and neutrophils (P = 1.6 × 10−7) in the pulmonary TB (PTB) samples compared to the control samples (Figure 2B, Supplementary Material Figure 1)
Summary
Tuberculosis (TB) is a chronic infectious lung disease caused by pathogenic Mycobacterium tuberculosis (MTB) belonging to the Mycobacteriaceae family. Despite the widespread use of antibiotics and live attenuated vaccine, TB remains to be the major cause of morbidity and death among all bacterial diseases [1]. This is primarily due to the rapid emergence of drug-resistant MTB strains and the incomplete knowledge of complex host-pathogen interactions [2]. Granulomas, hallmark of TB, are formed around the infected macrophages by the organized aggregation of immune cells (like T and B lymphocytes), multinucleated giant cells, dendritic cells, and fibroblasts. Granulomas suppress the host immune responses, as dendritic cells and macrophages were unable to present antigen to lymphocytes [4]. This study characterized the immune cell landscape and blood transcriptomic profile of patients with pulmonary TB (PTB) to identify the potential therapeutic biomarkers
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