Comparative Evaluation of MPT83 (Rv2873) for T Helper-1 Cell Reactivity and Identification of HLA-Promiscuous Peptides in Mycobacterium bovis BCG-Vaccinated Healthy Subjects

Mustafa, Abu Salim

doi:10.1128/cvi.05260-11

Cited by 16 publications

(18 citation statements)

References 65 publications

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“…The ProPred analysis has previously been shown to identify immunodominant antigens and peptides of several M. tuberculosis proteins [28]–[30], [39], [40]. The overall results of ProPred analysis suggest that PPE68 was a promiscuous HLA-DR binder (Table 3).…”

Section: Discussionmentioning

confidence: 96%

Characterization of a Cross-Reactive, Immunodominant and HLA-Promiscuous Epitope of Mycobacterium tuberculosis-Specific Major Antigenic Protein PPE68

Mustafa

2014

PLoS ONE

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PPE68 (Rv3873), a major antignic protein encoded by Mycobacteriun tuberculosis-specific genomic region of difference (RD)1, is a strong stimulator of peripheral blood mononuclear cells (PBMCs) obtained from tuberculosis patients and Mycobacterium bovis bacillus Calmette Guerin (BCG)-vaccianted healthy subjects in T helper (Th)1 cell assays, i.e. antigen-induced proliferation and interferon-gamma (IFN-γ) secretion. To confirm the antigen-specific recognition of PPE68 by T cells in IFN-γ assays, antigen-induced human T-cell lines were established from PBMCs of M. Bovis BCG-vaccinated and HLA-heterogeneous healthy subjects and tested with peptide pools of RD1 proteins. The results showed that PPE68 was recognized by antigen-specific T-cell lines from HLA-heteregeneous subjects. To further identify the immunodominant and HLA-promiscuous Th1-1 cell epitopes present in PPE68, 24 synthetic peptides covering the sequence of PPE68 were indivdually analyzed for HLA-DR binding prediction analysis and tested with PBMCs from M. bovis BCG-vaccinated and HLA-heterogeuous healthy subjects in IFN-γ assays. The results identified the peptide P9, i.e. aa 121-VLTATNFFGINTIPIALTEMDYFIR-145, as an immunodominant and HLA-DR promiscuous peptide of PPE68. Furthermore, by using deletion peptides, the immunodominant and HLA-DR promiscuous core sequence was mapped to aa 127-FFGINTIPIA-136. Interestingly, the core sequence is present in several PPE proteins of M. tuberculosis, and conserved in all sequenced strains/species of M. tuberculosis and M. tuberculosis complex, and several other pathogenic mycobacterial species, including M. leprae and M. avium-intracellulalae complex. These results suggest that the peptide aa 121–145 may be exploited as a peptide-based vaccine candidate against tuberculosis and other mycobacterial diseases.

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Section: Discussionmentioning

confidence: 96%

Characterization of a Cross-Reactive, Immunodominant and HLA-Promiscuous Epitope of Mycobacterium tuberculosis-Specific Major Antigenic Protein PPE68

Mustafa

2014

PLoS ONE

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“…Complex mycobacterial antigens and synthetic peptides of M. tuberculosis RD1. The complex mycobacterial antigens used in this study were whole-cell M. bovis BCG (ATCC 19015) [18], M. tuberculosis H37Rv [19], M. tuberculosis cell walls (MT-CW) [20], and M. tuberculosis culture filtrate (MT-CF) collected from in vitro midterm culture [21]. MT-CW and MT-CF were provided by J.T.…”

Section: Methodsmentioning

confidence: 99%

Comparative Analysis of Spontaneous and Mycobacterial Antigen‐Induced Secretion of Th1, Th2 and Pro‐Inflammatory Cytokines by Peripheral Blood Mononuclear Cells of Tuberculosis Patients

2012

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The cytokines produced by T helper (Th)1 cells (IFN‐γ, IL‐2 and TNF‐β) correlate with protection, whereas the cytokines released by Th2 cells (IL‐4, IL‐5) and the anti‐inflammatory cytokine IL‐10 correlate with pathogenesis of tuberculosis (TB). However, the pro‐inflammatory cytokines (IL‐1β, IL‐6, IL‐8, TNF‐α and IL‐12p70) are responsible for both protection and pathogenesis of TB. The aim of this work was to carry out a comparative analysis of cytokines present in early (day 2) and late (day 6) cultures of peripheral blood mononuclear cells (PBMCs) obtained from pulmonary tuberculosis patients. PBMCs were cultured in vitro in the absence and presence of exogenously added complex mycobacterial antigens and RD1 peptide pool. The supernatants were collected on day 2 and day 6 of culture and assayed for secreted cytokines using the flow cytomix assay. All of the cytokines, except for IL‐12p70, were spontaneously secreted by PBMCs of 27–100% TB patients, but only TNF‐α concentration was significantly higher on day 2 than day 6 (P < 0.05). Two days following antigenic stimulation, only IL‐1β, IL‐6, TNF‐α and IL‐10 were secreted in response to some mycobacterial antigens. However, 6 days later, all of the cytokines, except for IL‐2, IL‐4, IL‐5 and IL‐8, were secreted significantly in response to all complex antigens and RD1 peptides, compared with the non‐stimulated cultures (P < 0.05). In conclusion, the study shows that the longer in vitro stimulation time (6 days) was necessary for the optimal induction of IFN‐γ and TNF‐β, and practically convenient for the detection of IL‐10, IL‐1 β, TNF‐α and IL‐6.

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“…MPT83 is a surface‐exposed glycosylated lipoprotein that has widely been attributed to function in host cell adhesion. It is expressed as a strong immunogenic antigen in both M. tuberculosis and with 100% homology in M. bovis where it is called MPB83 . In cattle it induces strong T‐cell responses, and due to antibody generation as early as 4 weeks after infection it is a promising marker for serodiagnosis.…”

Section: Lipoprotein‐based Immunizationmentioning

confidence: 99%

Mycobacterium tuberculosis lipoproteins in virulence and immunity – fighting with a double‐edged sword

Becker

Sander

2016

FEBS Letters

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Bacterial lipoproteins are secreted membrane‐anchored proteins characterized by a lipobox motif. This lipobox motif directs post‐translational modifications at the conserved cysteine through the consecutive action of three enzymes: Lgt, LspA and Lnt, which results in di‐ or triacylated forms. Lipoproteins are abundant in all bacteria including Mycobacterium tuberculosis and often involved in virulence and immunoregulatory processes. On the one hand, disruption of the biosynthesis pathway of lipoproteins leads to attenuation of M. tuberculosis in vivo, and mycobacteria deficient for certain lipoproteins have been assessed as attenuated live vaccine candidates. On the other hand, several mycobacterial lipoproteins form immunodominant antigens which promote an immune response. Some of these have been explored in DNA or subunit vaccination approaches against tuberculosis. The immune recognition of specific lipoproteins, however, might also benefit long‐term survival of M. tuberculosis through immune modulation, while others induce protective responses. Exploiting lipoproteins as vaccines is thus a complex matter which requires deliberative investigation. The dual role of lipoproteins in the immunity to and pathogenicity of mycobacteria is discussed here.

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Comparative Evaluation of MPT83 (Rv2873) for T Helper-1 Cell Reactivity and Identification of HLA-Promiscuous Peptides in Mycobacterium bovis BCG-Vaccinated Healthy Subjects

Cited by 16 publications

References 65 publications

Characterization of a Cross-Reactive, Immunodominant and HLA-Promiscuous Epitope of Mycobacterium tuberculosis-Specific Major Antigenic Protein PPE68

Characterization of a Cross-Reactive, Immunodominant and HLA-Promiscuous Epitope of Mycobacterium tuberculosis-Specific Major Antigenic Protein PPE68

Comparative Analysis of Spontaneous and Mycobacterial Antigen‐Induced Secretion of Th1, Th2 and Pro‐Inflammatory Cytokines by Peripheral Blood Mononuclear Cells of Tuberculosis Patients

Mycobacterium tuberculosis lipoproteins in virulence and immunity – fighting with a double‐edged sword

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