Dataset Information

Increased vitamin D receptor expression from macrophages after stimulation with M. tuberculosis among persons who have recovered from extrapulmonary tuberculosis.

ABSTRACT:

Background

Independent of HIV infection, extrapulmonary TB (EPTB) risk is increased in women, persons of black race or foreign birth, and by genetic variants in vitamin D receptor (VDR), interleukin-1 beta (IL-1?), and toll-like receptor (TLR)-2; functional correlates are unclear. We evaluated macrophage expression of VDR, TLR2, cathelicidin, and TNF-?, and production of IL-1? in HIV-seronegative persons with previous EPTB, previous pulmonary TB, latent M. tuberculosis infection, and uninfected TB contacts. Persons with previous pleural TB were excluded due to enhanced immune responses at the site of disease.

Methods

Macrophages were stimulated with TLR-2 agonist M. tuberculosis lipoprotein (LpqH), live and gamma-irradiated M. tuberculosis.

Results

M. tuberculosis - infected macrophages from persons with previous EPTB had increased VDR expression (29.17 relative value unit increase in median expression vs. uninfected contacts, after adjusting for foreign-born status; P?=?0.02). Macrophages from persons with previous EPTB had a 38.88??g/mL increase in median IL-1? production after stimulation with LpqH compared to uninfected contacts (P?=?0.01); the effect was similar (44.99??g/mL) but not statistically significant after controlling for foreign-born status. Median 25-hydroxyvitamin D levels were low but not significantly different between groups.

Conclusions

There was increased macrophage expression of VDR after stimulation with live M. tuberculosis in persons with previous extrapulmonary TB. If post-treatment VDR expression reflects expression prior to disease, it may identify persons at risk for extrapulmonary TB.

SUBMITTER: Fiske CT

PROVIDER: S-EPMC6492421 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Increased vitamin D receptor expression from macrophages after stimulation with M. tuberculosis among persons who have recovered from extrapulmonary tuberculosis.

Fiske Christina T CT Blackman Amondrea A Maruri Fernanda F Rebeiro Peter F PF Huaman Moises M Kator Jamie J Scott Algood Holly M HM Sterling Timothy R TR

BMC infectious diseases 20190430 1

<h4>Background</h4>Independent of HIV infection, extrapulmonary TB (EPTB) risk is increased in women, persons of black race or foreign birth, and by genetic variants in vitamin D receptor (VDR), interleukin-1 beta (IL-1β), and toll-like receptor (TLR)-2; functional correlates are unclear. We evaluated macrophage expression of VDR, TLR2, cathelicidin, and TNF-α, and production of IL-1β in HIV-seronegative persons with previous EPTB, previous pulmonary TB, latent M. tuberculosis infection, and uni ...[more]

PMID: 31039752

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Project description:Persons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4(+) lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related to Mycobacterium tuberculosis infection of macrophages have not been characterized. The objective of this study was to further characterize the in vitro immune responses to M. tuberculosis infection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n = 11), previous pulmonary tuberculosis (n = 21), latent M. tuberculosis infection (n = 19), and uninfected tuberculosis contacts (n = 20). Experimental conditions included M. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1? (IL-1?), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-?), and gamma interferon (IFN-?) were measured by multiplex cytokine array. When M. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-? (P = 0.01), TNF-? (P = 0.04), IL-10 (P < 0.001), and IL-6 (P = 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latent M. tuberculosis infection. A similar pattern was observed with CXCL8 (P = 0.04), IL-10 (P = 0.02), and CCL2 (P = 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation with M. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response to M. tuberculosis infection.

Project description:BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB. METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection. RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1-negative individuals, and 0.85 in HIV-1-infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1. CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever. FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.

Dataset Information

Increased vitamin D receptor expression from macrophages after stimulation with M. tuberculosis among persons who have recovered from extrapulmonary tuberculosis.

Background

Methods

Results

Conclusions

Publications

Increased vitamin D receptor expression from macrophages after stimulation with M. tuberculosis among persons who have recovered from extrapulmonary tuberculosis.

Similar Datasets

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