Expression profiling of lymph nodes in tuberculosis patients reveal inflammatory milieu at site of infection

Abstract

Extrapulmonary manifestations constitute 15 to 20% of tuberculosis cases, with lymph node tuberculosis (LNTB) as the most common form of infection. However, diagnosis and treatment advances are hindered by lack of understanding of LNTB biology. To identify host response, Mycobacterium tuberculosis infected lymph nodes from LNTB patients were studied by means of transcriptomics and quantitative proteomics analyses. The selected targets obtained by comparative analyses were validated by quantitative PCR and immunohistochemistry. This approach provided expression data for 8,728 transcripts and 102 proteins, differentially regulated in the infected human lymph node. Enhanced inflammation with upregulation of T-helper1-related genes, combined with marked dysregulation of matrix metalloproteinases, indicates tissue damage due to high immunoactivity at infected niche. This expression signature was accompanied by significant upregulation of an immunoregulatory gene, leukotriene A4 hydrolase, at both transcript and protein levels. Comparative transcriptional analyses revealed LNTB-specific perturbations. In contrast to pulmonary TB-associated increase in lipid metabolism, genes involved in fatty-acid metabolism were found to be downregulated in LNTB suggesting differential lipid metabolic signature. This study investigates the tissue molecular signature of LNTB patients for the first time and presents findings that indicate the possible mechanism of disease pathology through dysregulation of inflammatory and tissue-repair processes.

Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis

“…One dataset, GSE63548, compared tuberculosis-infected lymph node tissue to lymph nodes from healthy controls; 31 here, the tuberculosis score had an ROC AUC of 0·98 (appendix p 18). However, because this study was conducted in actual lymph node tissue, not peripheral blood, further work will be needed to assess the use of the tuberculosis score in extrapulmonary tuberculosis.…”

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

“…BCL6 has been shown to mediate a sustained Mtb specific CD4 T cell response in addition to regulating host apoptotic responses (Moguche et al, 2015). Both IFI44L and SLPI participate in the interferon-mediated inflammation in TB (Maji et al, 2015), with IFI44L also implicated in lymph node tuberculosis; SLPI has been shown to exhibit antimicrobial activity and also plays an important role in regulating apoptosis by interacting with membrane phospholipid scramblase (Py et al, 2009). …”

Two-Year Follow-up Study of Mycobacterium tuberculosis Antigen-Driven IFN-γ Responses and Macrophage sCD14 Levels After Tuberculosis Contact

“…It is accepted that host genetic background plays a role in the susceptibility to TB, restricting the infection or leading to active TB development [21]. The genetically determined mechanisms that underlie the initiation and maintenance of immune responses against M.tb involve many different immune parameters as well as various immune cell types [22,23]. Genetic differences that affect the functions of these cells can generate the imbalance between M.tb and the host immunity, thus influencing the outcome of the mycobacteria-host interactions.…”