ESAT6-Induced IFNγ and CXCL9 Can Differentiate Severity of Tuberculosis

Hasan, Zahra; Jamil, Bushra; Ashraf, Muhammad Waqar; Islam, Muniba; Yusuf, M. S.; Khan, Javaid Ahmed; Hussain, Rabia

doi:10.1371/journal.pone.0005158

Cited by 36 publications

(34 citation statements)

References 41 publications

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“…Second, extrapulmonary TB is a complex disease, and different sites of disease manifestation may have different pathophysiology (9,26,34,37). Previous studies have suggested that persons with different sites of TB disease have various immune responses (18). We included a wide spectrum of TB manifestations in the present study.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

Fiske

Almeida

Shintani

et al. 2012

Clin. Vaccine Immunol.

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T uberculosis (TB) presents an interesting paradox: while onethird of the world's population is infected with Mycobacterium tuberculosis, only 5 to 10% of those infected will develop active disease (1,23). This observation suggests that factors other than the mycobacterium play a role in the development of TB. Our understanding of protective immunity to M. tuberculosis infection is incomplete. The immune response to M. tuberculosis involves cells such as monocytes, macrophages, and T lymphocytes that produce cytokines such as CXCL8 (interleukin-8 [IL-8]), IL-12, gamma interferon (IFN-␥), and tumor necrosis alpha (TNF-␣) (16). While hematogenous dissemination occurs in most persons soon after infection, subsequent extrapulmonary TB disease does not (25). Development of extrapulmonary disease could be a result of a breakdown in host immune surveillance, a change in the mycobacteria from a dormant to an active state, or a combination of the two. Discovery of factors that predispose to extrapulmonary disease will advance TB prevention efforts by identifying immune responses that could be boosted by TB vaccines. It will also help identify individuals at increased risk for progression from latent infection to clinical disease, so that more intensive observation and treatment of latent infection can be initiated.Extrapulmonary TB is associated with underlying immune defects. For example, HIV-infected persons are at increased risk of extrapulmonary TB, and this risk increases as the CD4 ϩ T lymphocyte count declines (30). Young children also have an increased incidence of extrapulmonary TB, specifically TB meningitis, presumably due to an immature immune system (31). Our group has previously noted reduced peripheral blood mononuclear cell (PBMC) cytokine production and CD4 ϩ T lymphocytes in HIV-seronegative adults with previous extrapulmonary TB compared to persons with previous pulmonary TB or latent M. tuberculosis infection (2, 38). In a subset of patients from the present study, we also found that persons with previous extrapulmonary TB had increased regulatory T cell frequency and CD4 ϩ lymphocyte activation, indicating possible immune dysregulation (8). However, an evaluation of the sequential activation of innate and adaptive immune responses to M. tuberculosis infection in such patients has not been performed. We therefore assessed in vitro immune responses in persons with previous extrapulmonary TB under several experimental conditions, including one in which autologous monocyte-depleted PBMCs were cocultured with M. tuberculosis-infected host macrophages.

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Section: Discussionmentioning

confidence: 99%

Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

Fiske

Almeida

Shintani

et al. 2012

Clin. Vaccine Immunol.

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“…Recombinant human IFN-γ was used to obtain a dose response curve with a range of detection from 3.9-1000 pg/ml. All experimental samples were tested in duplicate [21].…”

Section: Measurement Of Ifn-γmentioning

confidence: 99%

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

Masood

Hussain

Rao

et al. 2014

J Infect Dev Ctries

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Introduction: 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. Methodology: 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. Results: 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. Conclusion: 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.

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“…CCL2 has also been suggested to be a biomarker for TB [18]. Both CXCL10 and CCL2 have been suggested to be useful for discrimination between individuals with and without tuberculosis infections [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…As cytokine and chemokine responses to Mycobacterium and to mycobacterial antigens, ESAT-6 and CFP-10 differ in patients with pulmonary (PTB) or extrapulmonary (EPTB) disease [19]. The utility of CXCL9, CXCL10 and CCL2 has been addressed as additional biomarkers in conjunction with ESAT6-induced IFN-c responses to diagnose TB in a highly endemic, BCG-vaccination population.…”

Section: Introductionmentioning

confidence: 99%

Measurement of ESAT6-induced IFNγ responses adjunct with CXCL9 increases the rate of diagnosis of active tuberculosis in an endemic region

Hasan¹,

Rao²,

Salahuddin³

et al. 2013

International Journal of Mycobacteriology

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Due to difficulties in direct diagnosis of Mycobacterium tuberculosis infection where site-specific specimens are not available, indirect methods of testing for infection are required. M. tuberculosis early secreted antigen target-6 (ESAT6) induced IFN-γ responses are specific, but do not differentiate between latent and active TB. The use of adjunct biomarkers for TB diagnosis has been proposed, such as the chemokines: CXCL9, CXCL10 and CCL2. ESAT6-induced IFN-γ CXCL9, CXCL10 and CCL2 was measured in whole blood cell supernatants of patients with pulmonary tuberculosis (PTB, n=36) and extrapulmonary TB (ETB, n=31) and compared with healthy endemic controls (EC, n=33). ESAT6-induced IFN-γ responses were positive in 32% of TB cases as compared with 15% of EC cases (p=0.048). ESAT6-induced CXCL9 responses were positive in 42% of TB cases and 15% of EC cases (p=0.006). ESAT6-induced-CXCL10 and -CCL2 responses did not discriminate between TB and EC groups. Measurement of IFN-γ or CXCL9 together diagnosed TB (53%) cases and was significant as compared with EC (p=0.014) cases. IFN-γ and CXCL10 together did not increase the number of TB cases diagnosed. Within TB groups, ESAT6-IFN-γ/CXCL9-based detection increased to 53% in PTB (p=0.031) and 54% in ETB (p=0.021), with comparable diagnosis in less severe extrapulmonary TB (L-ETB, 55%) and severe disseminated extrapulmonary TB (D-ETB, 50%). Given that 47% of TB cases remained undetected, this study shown that ESAT6-induced IFNγ and CXCL9 can support diagnosis, but must be supported by clinical correlation and other relevant investigations.

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ESAT6-Induced IFNγ and CXCL9 Can Differentiate Severity of Tuberculosis

Cited by 36 publications

References 41 publications

Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

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

Measurement of ESAT6-induced IFNγ responses adjunct with CXCL9 increases the rate of diagnosis of active tuberculosis in an endemic region

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