Phenolic-glycolipid-1 and lipoarabinomannan preferentially modulate TCR- and CD28-triggered proximal biochemical events, leading to T-cell unresponsiveness in mycobacterial diseases

Dagur, Pradeep K.; Sharma, Bhawna; Upadhyay, Rajni; Dua, Bhavyata; Rizvi, Arshad; Khan, Naim Akhtar; Katoch, Vishwa Mohan; Sengupta, Utpal; Joshi, Beenu

doi:10.1186/1476-511x-11-119

Cited by 12 publications

(11 citation statements)

References 34 publications

(39 reference statements)

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“…Similarly, a significantly reduced baseline IFN-c and TNF-a response to LAM in contacts may suggest initially suppressed pro-inflammatory cytokines probably related to bacterial multiplication. LAM is known to suppress activation of adaptive immunity through direct T cell inhibition by blocking ZAP-70, Lck and LAT phosphorylation as well as interfering with early events in T cell receptor signaling as reported earlier (14,15,23). However, it could also be due to early infection with absence of established adaptive immunity.…”

Section: Discussionmentioning

confidence: 86%

Lipoarabinomannan‐specific TNF‐α and IFN‐γ as markers of protective immunity against tuberculosis: a cohort study in an endemic setting

Belay

Legesse

Mihret

et al. 2015

APMIS

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Lipoarabinomannan (LAM) is a virulent factor used for entry and survival of Mycobacterium tuberculosis (Mtb) in macrophages. Although the role of LAM for the diagnosis of tuberculosis (TB) has been extensively investigated, its cytokine response during natural Mtb infection in humans is largely unknown. In this study, LAM-specific IFN-γ, TNF-α, and IL-10 levels following whole blood assay were measured in untreated pulmonary TB patients, their contacts and community controls at baseline. In treated patients and contacts, cytokines were also measured at 6 and 12 months. At entry, 52.8% and 74.8% of controls and contacts were QFT-GIT positive, respectively. At baseline, untreated TB patients and contacts had significantly lower IFN-γ and TNF-α response compared to community controls (p < 0.0001). Besides, untreated patients had significantly higher TNF-α and IL-10 response compared to their contacts (p < 0.0001). At 6 months, contacts and treated TB patients had significantly increased INF-γ and TNF-α response (p < 0.0001). In TB patients, IFN-γ increased 10-fold following chemotherapy suggesting its potential role for treatment monitoring. The data suggests that LAM might have an anti-inflammatory effect during clinical TB and early Mtb infection. The data also suggests that LAM-induced IFN-γ and TNF-α could be used as biomarkers of protective immunity.

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Section: Discussionmentioning

confidence: 86%

Lipoarabinomannan‐specific TNF‐α and IFN‐γ as markers of protective immunity against tuberculosis: a cohort study in an endemic setting

Belay

Legesse

Mihret

et al. 2015

APMIS

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“…Similar to our findings differential modulation of downstream signalling events like MAPKs by M. leprae antigens stimulated T cells from leprosy patients have been reported earlier [ 16 , 17 ]. Further, diminished and differential phosphorylation of MAPKs by M. leprae antigens in T cell lines after stimulation with anti CD3 or anti CD3+CD28 has also been reported [ 18 , 19 ]. Effect of secretory protein ESAT-6 of M. tuberculosis in the modulation of macrophage signalling pathways particularly ERK1/2 MAPK pathway has been shown in one study [ 23 ].…”

Section: Discussionmentioning

confidence: 98%

“…Present study confirms that mycobaterial antigens: Ag85A, ESAT-6, PPD and H37Rv, altered calcium signalling and consequently might play a critical role in the pathogenesis of the disease. Altered calcium signalling and other signalling events has been noted in leprosy patients and T cell lines and modulation by lipid and soluble fraction of M. leprae lysates was shown which could play a major role in the pathogenesis [ 15 – 19 ]. Our results are in close concordance with other reports where PBMCs from patients with leprosy have been reported to have reduced cytosolic [Ca +2 ]i concentrations [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

et al. 2015

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BackgroundMycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The molecules and mechanisms utilized to accomplish immune subversion by M. tuberculosis are not fully understood. Understanding the molecular mechanism of T cell response to M. tuberculosis is important for development of efficacious vaccine against TB.MethodsHere, we investigated effect of M. tuberculosis antigens Ag85A and ESAT-6 on T cell signalling events in CD3/CD28 induced Peripheral blood mononuclear cells (PBMCs) of PPD+ve healthy individuals and pulmonary TB patients. We studied CD3 induced intracellular calcium mobilization in PBMCs of healthy individuals and TB patients by spectrofluorimetry, CD3 and CD28 induced activation of mitogen activated protein kinases (MAPKs) in PBMCs of healthy individuals and TB patients by western blotting and binding of transcription factors NFAT and NFκB by Electrophorectic mobility shift assay (EMSA).ResultsWe observed CD3 triggered modulations in free intracellular calcium concentrations in PPD+ve healthy individuals and pulmonary TB patients after the treatment of M. tuberculosis antigens. As regards the downstream signalling events, phosphorylation of MAPKs, Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 was curtailed by M. tuberculosis antigens in TB patients whereas, in PPD+ve healthy individuals only ERK1/2 phosphorylation was inhibited. Besides, the terminal signalling events like binding of transcription factors NFAT and NFκB was also altered by M. tuberculosis antigens. Altogether, our results suggest that M. tuberculosis antigens, specifically ESAT-6, interfere with TCR/CD28-induced upstream as well as downstream signalling events which might be responsible for defective IL-2 production which further contributed in T-cell unresponsiveness, implicated in the progression of disease.ConclusionTo the best of our knowledge, this is the first study to investigate effect of Ag85A and ESAT-6 on TCR- and TCR/CD28- induced upstream and downstream signalling events of T-cell activation in TB patients. This study showed the effect of secretory antigens of M. tuberculosis in the modulation of T cell signalling pathways. This inflection is accomplished by altering the proximal and distal events of signalling cascade which could be involved in T-cell dysfunctioning during the progression of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0128-6) contains supplementary material, which is available to authorized users.

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“…One of the hallmarks of the disease is its bipolar manifestation across a spectrum of intermediate forms. Anergy in LL seems to implicate triggering by microbial components and impairment of pathways leading to IL-2 production, a key proliferation factor for T cells (Dagur et al 2010(Dagur et al , 2012. The form and severity of the disease seem to depend on both the virulence of M. leprae (Han et al 2008(Han et al , 2009 and the characteristics of the host because highly susceptible individuals develop LL, while more resistant individuals develop TT (Marquet & Schurr 2001).…”

mentioning

confidence: 99%

“…Anergy does not occur in TT, in which the disease evolves less aggressively and often disappears in a spontaneous manner. Anergy in LL seems to implicate triggering by microbial components and impairment of pathways leading to IL-2 production, a key proliferation factor for T cells (Dagur et al 2010(Dagur et al , 2012. We hypothesized that because it is a microbial-induced T-cell defect, anergy might be reversed or modulated by the use of immunomodulators such as transfer factor (TF) from sensitized donors.…”

mentioning

confidence: 99%

Induction and treatment of anergy in murine leprosy

Juárez-Ortega¹,

Hernandez²,

Arce‐Paredes³

et al. 2014

Int J Experimental Path

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Leprosy is a disease consisting of a spectrum of clinical, bacteriological, histopathological and immunological manifestations. Tuberculoid leprosy is frequently recognized as the benign polar form of the disease, while lepromatous leprosy is regarded as the malignant form. The different forms of leprosy depend on the genetic and immunological characteristics of the patient and on the characteristics of the leprosy bacillus. The malignant manifestations of lepromatous leprosy result from the mycobacterial-specific anergy that develops in this form of the disease. Using murine leprosy as a model of anergy in this study, we first induced the development of anergy to Mycobacterium lepraemurium (MLM) in mice and then attempted to reverse it by the administration of dialysable leucocyte extracts (DLE) prepared from healthy (HLT), BCG-inoculated and MLM-inoculated mice. Mice inoculated with either MLM or BCG developed a robust cell-mediated immune response (CMI) that was temporary in the MLM-inoculated group and long-lasting in the BCG-inoculated group. DLE were prepared from the spleens of MLM- and BCG-inoculated mice at the peak of CMI. Independent MLM intradermally-inoculated groups were treated every other day with HLT-DLE, BCG-DLE or MLM-DLE, and the effect was documented for 98 days. DLE administered at a dose of 1.0 U (1 × 10(6) splenocytes) did not affect the evolution of leprosy, while DLE given at a dose of 0.1 U showed beneficial effects regardless of the DLE source. The dose but not the specificity of DLE was the determining factor for reversing anergy.

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Phenolic-glycolipid-1 and lipoarabinomannan preferentially modulate TCR- and CD28-triggered proximal biochemical events, leading to T-cell unresponsiveness in mycobacterial diseases

Cited by 12 publications

References 34 publications

Lipoarabinomannan‐specific TNF‐α and IFN‐γ as markers of protective immunity against tuberculosis: a cohort study in an endemic setting

Lipoarabinomannan‐specific TNF‐α and IFN‐γ as markers of protective immunity against tuberculosis: a cohort study in an endemic setting

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

Induction and treatment of anergy in murine leprosy

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