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

Christina T Fiske,Jamie Kator,Moises Huaman,Amondrea Blackman,Fernanda Maruri,Holly M Scott Algood,Timothy R Sterling,Peter F Rebeiro

doi:10.1186/s12879-019-3958-7

Abstract

BackgroundIndependent 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.MethodsMacrophages were stimulated with TLR-2 agonist M. tuberculosis lipoprotein (LpqH), live and gamma-irradiated M. tuberculosis.ResultsM. 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.ConclusionsThere 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.

Highlights

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 found that macrophages from persons with previous extrapulmonary TB produced significantly more Interleukin 1 beta (IL-1β) twenty-four hours after stimulation with the 19 kDa M. tuberculosis 19Kda lipoprotein (LpqH) compared to uninfected persons (Table 3)
We found that M. tuberculosis-stimulated macrophages from persons with previous extrapulmonary TB had higher expression of VDR compared to macrophages from persons with previous pulmonary TB, TB contacts with latent M. tuberculosis infection, and uninfected contacts

Summary

Introduction

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. TB, presents a conundrum: while one-quarter to one-third of the world’s population is infected with M. tuberculosis, [2, 3] only 5–10% of those infected develop active disease [4,5,6]. This indicates that factors other than the mycobacterium play an important role in TB pathogenesis. Identifying factors that facilitate reactivation of infection, extrapulmonary dissemination, and active disease will advance TB prevention efforts by focusing on the small minority of persons at risk of developing active TB, as well as protective immune responses that could be augmented by TB vaccines

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