ABSTRACT
Host responses following exposure to Mycobacterium tuberculosis (TB) are complex and can significantly affect clinical outcome. These responses, which are largely mediated by complex immune mechanisms involving peripheral blood cells (PBCs) such as T-lymphocytes, NK cells and monocyte-derived macrophages, have not been fully characterized. We hypothesize that different clinical outcome following TB exposure will be uniquely reflected in host gene expression profiles, and expression profiling of PBCs can be used to discriminate between different TB infectious outcomes. In this study, microarray analysis was performed on PBCs from three TB groups (BCG-vaccinated, latent TB infection, and active TB infection) and a control healthy group. Supervised learning algorithms were used to identify signature genomic responses that differentiate among group samples. Gene Set Enrichment Analysis was used to determine sets of genes that were co-regulated. Multivariate permutation analysis (p < 0.01) gave 645 genes differentially expressed among the four groups, with both distinct and common patterns of gene expression observed for each group. A 127-probeset, representing 77 known genes, capable of accurately classifying samples into their respective groups was identified. In addition, 13 insulin-sensitive genes were found to be differentially regulated in all three TB infected groups, underscoring the functional association between insulin signaling pathway and TB infection.
Subject(s)
Antigens, Bacterial/immunology , Killer Cells, Natural/immunology , Macrophage Activation/immunology , Macrophages/immunology , Mycobacterium tuberculosis/pathogenicity , T-Lymphocytes/immunology , Transcriptional Activation , Tuberculosis/immunology , Aged , Cluster Analysis , Female , Genetic Predisposition to Disease , Humans , Latent Tuberculosis/immunology , Macrophage Activation/genetics , Male , Microarray Analysis , Middle Aged , Multivariate Analysis , Mycobacterium tuberculosis/genetics , Polymorphism, Single Nucleotide , Reagent Kits, Diagnostic , Reproducibility of Results , Signal Transduction , Tuberculosis/geneticsABSTRACT
Mycobacterium tuberculosis (MTB) is a leading cause of mortality worldwide from an infectious agent. Natural killer T (NKT) cells recognize mycobacterial antigens and contribute to anti-MTB immunity in mouse models. NKT cells were measured in subjects with pulmonary tuberculosis, MTB-exposed individuals, and healthy controls. NKT cell levels are selectively lower in peripheral blood mononuclear cells from individuals with pulmonary tuberculosis than in both MTB-exposed subjects and healthy control subjects. This apparent loss of NKT cells from the peripheral blood is sustained during the 6 months after the initiation of MTB treatment. These findings indicate that NKT cells may be an important component of antituberculosis immunity.
