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. 2019 Apr 30;19(1):366.
doi: 10.1186/s12879-019-3958-7.

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

Christina T Fiske  1   2 , Amondrea Blackman  3   4 , Fernanda Maruri  3   4 , Peter F Rebeiro  3   4   5 , Moises Huaman  6 , Jamie Kator  7 , Holly M Scott Algood  3   4   8 , Timothy R Sterling  3   4
Affiliations

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

Christina T Fiske et al. BMC Infect Dis. .

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-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 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 μg/mL increase in median IL-1β production after stimulation with LpqH compared to uninfected contacts (P = 0.01); the effect was similar (44.99 μg/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.

Keywords: Extrapulmonary tuberculosis; Interleukin-1 beta; M. Tuberculosis; Toll-like receptor 2; Vitamin D receptor.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Institutional Review Boards of Vanderbilt University Medical Center, Metro Public Health Department, and the Tennessee Department of Health. All participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Violin plot showing medians and distributions of VDR expression (relative units) by patient group and macrophage stimulation condition. Expression of vitamin D receptor (VDR) in PBMC derived macrophages from uninfected persons, latently infected persons and persons with previous pulmonary TB and previous extrapulmonary TB after overnight stimulation. Macrophages were stimulated for two hours with live M. tuberculosis (H37Rv, MOI 5–10), gamma-irradiated M. tuberculosis (10 μg/mL), and M. tuberculosis lipoprotein (LpqH, 10 μg/mL). VDR expression levels were assessed by qPCR and normalized to Gapdh levels. Experiments were performed in duplicate
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