Soluble markers of the Toll-like receptor 4 pathway differentiate between active and latent tuberculosis and are associated with treatment responses.

Siri L Feruglio,Dag Kvale,Marius Trøseid,Anne Ma Dyrhol-Riise,Jan Kristian Damås,Delia Goletti

doi:10.1371/journal.pone.0069896

Abstract

BackgroundBiomarkers to differentiate between active tuberculosis (TB) and latent TB infection (LTBI) and to monitor treatment responses are requested to complement TB diagnostics and control, particularly in patients with multi-drug resistant TB. We have studied soluble markers of the Toll-like-receptor 4 (TLR-4) pathway in various stages of TB disease and during anti-TB treatment.MethodsPlasma samples from patients with culture confirmed drug-sensitive TB (n = 19) were collected before and after 2, 8 and 24 weeks of efficient anti-TB treatment and in a LTBI group (n = 6). Soluble (s) CD14 and myeloid differentiation-2 (MD-2) were analyzed by the Enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) was analyzed by the Limulus Amebocyte Lysate colorimetric assay. Nonparametric statistics were applied.ResultsPlasma levels of sCD14 (p<0.001), MD-2 (p = 0.036) and LPS (p = 0.069) were elevated at baseline in patients with untreated active TB compared to the LTBI group. MD-2 concentrations decreased after 2 weeks of treatment (p = 0.011), while LPS levels decreased after 8 weeks (p = 0.005). In contrast, sCD14 levels increased after 2 weeks (p = 0.047) with a subsequent modest decrease throughout the treatment period. There was no significant difference in concentrations of any of these markers between patients with pulmonary and extrapulmonary TB or between patients with or without symptoms.ConclusionOur data suggest that plasma levels of LPS, MD-2 and sCD14 can discriminate between active TB and LTBI. A decline in LPS and MD-2 concentrations was associated with response to anti-TB treatment. The clinical potential of these soluble TLR-4 pathway proteins needs to be further explored.

Highlights

Tuberculosis (TB) is a global challenge and there were an estimated 8.7 million incident cases in 2011, 13% were co-infected with human immunodeficiency virus (HIV) and 20% of previously treated cases had multi-drug resistant (MDR)-TB [1]
Our pilot study indicates that plasma levels of LPS and myeloid differentiation-2 (MD-2) can discriminate between various stages of TB disease and possibly predict responses to therapy
Plasma levels of LPS at baseline were higher, not significant, in the active TB group compared to the latent TB infection (LTBI) group (60 pg/mL [44–77] vs. 39 pg/mL [31–63], p = 0.069) (Fig. 2A)

Summary

Introduction

Tuberculosis (TB) is a global challenge and there were an estimated 8.7 million incident cases in 2011, 13% were co-infected with human immunodeficiency virus (HIV) and 20% of previously treated cases had multi-drug resistant (MDR)-TB [1] Both TB culture, which is the diagnostic gold standard, and the Xpert MTB/ RIF assay often fail in cases of extrapulmonary TB, in HIVinfection and in children [2] and TB diagnosis is often made on clinical criteria. Several meta-analyses show that the cellular interferon- gamma- release- assays (IGRAs) are at least as sensitive and more specific than the tuberculin skin test (TST) [10,11,12,13] Still, they do not discriminate between latent TB infection (LTBI) and active TB and cannot monitor therapy. We have studied soluble markers of the Toll-like-receptor 4 (TLR-4) pathway in various stages of TB disease and during anti-TB treatment

Methods

Results

Conclusion