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Evaluation of gamma interferon immune response elicited by the newly constructed PstS-1(285-374):CFP10 fusion protein to detect Mycobacterium tuberculosis infection.

ABSTRACT: The PstS1 antigen is highly immunogenic, principally when combined with CFP10 during both latent and active TB infection. In the present study, a selected pstS1 gene fragment was cloned, fused with CFP10, and expressed in Escherichia coli. The product [PstS-1(285-374):CFP10] was compared to the recombinant fused RD1 (region of deletion 1) protein (ESAT-6:CFP10) in detecting Mycobacterium tuberculosis infection in 108 recent contacts of pulmonary tuberculosis (TB) cases, considering a positive tuberculin skin test (TST) to be the baseline. The release of gamma interferon (IFN-?) in 22-h whole-blood and 5-day lymphocyte stimulation assays primed with each antigen was determined. All contacts were clinically followed for up to 1 year, and 87% of the tuberculin skin test-positive (TST(positive)) patients accepted preventative treatment. Concerning the IFN-? response to PstS-1(285-374):CFP10 in the 22-h and 5-day assays, a slight increase in contact-TST(positive) detection was observed (23/54 and 26/54) compared to the level seen with the RD1 protein (18/54 and 24/54) whereas in the TST(negative) group, similarly lower numbers (?5/48) of responders were achieved for both antigens, except for RD1 in the 5-day assay (8/48). By combining the IFN-? responders to both antigens in the 5-day assays, slightly higher increases in positivity were found in the TST(positive) (32/54) and TST(negative) (10/48) groups. Two of 12 untreated TST(positive) contacts progressed to active TB and were concordantly positive in all assays, except for one contact who lacked positivity in the RD1 5-day assay. We demonstrated for the first time that PstS-1(285-374):CFP10 slightly increased contact positivity and detection of active disease progression, suggesting its potential application as a TB infection marker.

SUBMITTER: Araujo LS

PROVIDER: S-EPMC3993111 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Evaluation of gamma interferon immune response elicited by the newly constructed PstS-1(285-374):CFP10 fusion protein to detect Mycobacterium tuberculosis infection.

Araujo Leonardo Silva de LS Mello Fernanda Carvalho de Queiroz FC Silva Nidai de Bárbara Moreira da Nde B Leung Janaina Aparecida Medeiros JA Machado Silvia Maria Almeida SM Sardella Isabela Gama IG Maciel Renata de Moraes Rde M Saad Maria Helena Féres MH

Clinical and vaccine immunology : CVI 20140212 4

The PstS1 antigen is highly immunogenic, principally when combined with CFP10 during both latent and active TB infection. In the present study, a selected pstS1 gene fragment was cloned, fused with CFP10, and expressed in Escherichia coli. The product [PstS-1(285-374):CFP10] was compared to the recombinant fused RD1 (region of deletion 1) protein (ESAT-6:CFP10) in detecting Mycobacterium tuberculosis infection in 108 recent contacts of pulmonary tuberculosis (TB) cases, considering a positive tu ...[more]

PMID: 24521785

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Project description:In Chagas disease, CD8(+) T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8(+) T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8(+) T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8(+) T-cell capacity to produce interferon-gamma (IFN?) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8(+) T-cells segregated into IFN?(+) perforin (Pfn)(neg) or IFN?(neg)Pfn(+) cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8(+)Pfn(+) cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8(-/-) recipients showed that the CD8(+) cells from infected ifn?(-/-)pfn(+/+) donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8(+) cells from ifn?(+/+)pfn(-/-) donors. Moreover, the reconstitution of naïve cd8(-/-) mice with CD8(+) cells from naïve ifn?(+/+)pfn(-/-) donors ameliorated T. cruzi-elicited heart injury paralleled IFN?(+) cells accumulation, whereas reconstitution with CD8(+) cells from naïve ifn?(-/-)pfn(+/+) donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn(+) cells in the cardiac tissue. Our data support a possible antagonist effect of CD8(+)Pfn(+) and CD8(+)IFN?(+) cells during CCC. CD8(+)IFN?(+) cells may exert a beneficial role, whereas CD8(+)Pfn(+) may play a detrimental role in T. cruzi-elicited heart injury.

Project description:ObjectiveFamilial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon-γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ-blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH.MethodsIFNγ-/- Prf1-/- mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell-intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin-33 (IL-33)/ST2 blockade were performed using monoclonal antibodies.ResultsLCMV infection of IFNγ-/- Prf1-/- mice resulted in severe HLH-like disease. CD8+ T cells and the IL-33/ST2 axis remained essential mediators of disease; however, IFNγ-independent HLH immunopathology correlated with a 10-15-fold increase in neutrophilia (P < 0.001) and an altered cytokine milieu dominated by IL-6, IL-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM-CSF and neutrophil survival.ConclusionIFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider case-by-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ-dependent and -independent manifestations of HLH/MAS.

Dataset Information

Evaluation of gamma interferon immune response elicited by the newly constructed PstS-1(285-374):CFP10 fusion protein to detect Mycobacterium tuberculosis infection.

Publications

Evaluation of gamma interferon immune response elicited by the newly constructed PstS-1(285-374):CFP10 fusion protein to detect Mycobacterium tuberculosis infection.

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