Soluble Markers of the Toll-Like Receptor 4 Pathway Differentiate between Active and Latent Tuberculosis and Are Associated with Treatment Responses

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.

Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

“…sCD14 and sCD163 are markers of monocyte/macrophage activation and their levels in the blood usually reflect chronic immune activation involving myeloid cells [21]. In addition, sCD163 and sCD14 have been shown previously to server as plasma markers of active TB [22], [23]. PDGF is a pro-fibrotic growth factor that has been directly linked to increased fibrosis in TB patients [24].…”

Tuberculosis Biomarkers: From Diagnosis to Protection

“…Besides IGRA, several approaches for LTBI identification have been proposed: evaluation of plasma concentrations of epidermal growth factor fractalkine, IFNγ, IL4, monocyte chemoattractant protein (MCP)3, IP10; 126 evaluation of serum pro-inflammatory cytokines IL6, IP10, MCP1; 127 detection of plasma levels of markers involved in the Toll-like receptor 4 pathway, like soluble CD14 and myeloid differentiation-2. 128 A recent study on LTBI subjects demonstrated that Mtb-specific CD4+ T-cells have a characteristic chemokine expression signature (CCR6 + CXCR3 + CCR4 - ), and that the frequency of these cells is increased in LTBI subjects compared with healthy donors (129). This study suggested a possible role of specific subsets of CD4 + T-cells in the containment of Mtb and raises interesting questions on the possible role of these cells.…”

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…Plasma levels of markers involved in the Toll-like receptor 4 pathway, like soluble CD14 (sCD14) and myeloid differentiation-2 (MD-2), have furthermore been shown to differentiate between latently infected individuals and TB patients (Feruglio et al 2013). …”