Differential Early Secreted Antigen Target (ESAT) 6 kDa–induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis

Kiran Iqbal Masood,Zahra Hasan,Muhammad Irfan,Rabia Hussain,Martin E Rottenberg,Naseem Salahuddin,Nisar Rao

doi:10.3855/jidc.3412

Abstract

Expression of Suppressor of cytokine signaling (SOCS)-1 molecules is increased in patients with tuberculosis (TB). Early Secreted Antigen Target (ESAT)-6 kDa - induced IFN-γ responses indicate Mycobacterium tuberculosis infection. The effect of ESAT6- stimulation on SOCS1 in the host is not known. Healthy asymptomatic controls had a negative (n = 16) or a positive ( n = 13) tuberculin skin test (TST). ESAT6-induced IFN-γ responses classified these controls as positive (EC ESAT6 IFN-γ (+), n = 5) or negative (EC ESAT6 IFN-γ (-), n = 24) responders. Patients had pulmonary (n = 21) or extra-pulmonary (n = 30) tuberculosis. Peripheral blood cells were stimulated with ESAT6 and mRNA expression of IFN-γ and SOCS1 was determined. ESAT6-induced IFN-γ expression was raised in EC ESAT6 IFN-γ (+) as compared with EC ESAT6 IFN-γ (-), p = 0.019. ESAT6-induced SOCS1 mRNA expression was increased in both pulmonary TB and extra-pulmonary TB patients as compared with both EC groups. ESAT6-induced IFN-γ/SOCS1 mRNA expression ratio was decreased in TB patients as compared with both EC groups. M. tuberculosis infection induces increased ESAT6-induced IFN-γ responses in both latent and active TB. Our data shows down-regulation of IFN-γ / SOCS1 expression to be induced only in active TB cases, distinguishing them from healthy individuals likely to have latent TB. A decreasing IFN-γ /SOCS1 ratio may leads to reduced Th1 immunity which contributes to inability of the host to control clinical disease.

Highlights

Expression of Suppressor of cytokine signaling (SOCS)-1 molecules is increased in patients with tuberculosis (TB)
The Tuberculin skin test (TST) reaction is still commonly used to identify individuals who have been exposed to M. tuberculosis but this has been shown to be a non-specific test due to cross reactivity with other mycobacterial antigens and because it is affected by BCG vaccination of the host [2]
As Interferon gamma release assays (IGRAs) rely on a competent IFN-γ response which is affected by SOCS1 molecules we investigated ESAT6-induced IFN-γ and SOCS1 mRNA expression levels in patients with TB and healthy endemic controls

Summary

Introduction

Expression of Suppressor of cytokine signaling (SOCS)-1 molecules is increased in patients with tuberculosis (TB). Secreted Antigen Target (ESAT)-6 kDa – induced IFN-γ responses indicate Mycobacterium tuberculosis infection. ESAT6induced SOCS1 mRNA expression was increased in both pulmonary TB and extra-pulmonary TB patients as compared with both EC groups. ESAT6-induced IFN-γ/SOCS1 mRNA expression ratio was decreased in TB patients as compared with both EC groups. Our data shows down-regulation of IFN- γ / SOCS1 expression to be induced only in active TB cases, distinguishing them from healthy individuals likely to have latent TB. The Tuberculin skin test (TST) reaction is still commonly used to identify individuals who have been exposed to M. tuberculosis but this has been shown to be a non-specific test due to cross reactivity with other mycobacterial antigens and because it is affected by BCG vaccination of the host [2]. In murine and human models of tuberculosis ESAT-6–specific, IFN-γ– secreting CD4 T cells have been shown to play a role

Methods

Results

Conclusion