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Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response.

ABSTRACT: Overcoming drug-resistance is one of the major challenges to control tuberculosis (TB). The up-regulation of efflux pumps is one common mechanism that leads to drug-resistance. Therefore, immunotherapy targeting these efflux pump antigens could be promising strategy to be combined with current chemotherapy. Considering that CD8+ cytotoxic T lymphocytes (CTLs) induced by antigenic peptides (epitopes) could elicit HLA-restricted anti-TB immune response, efflux pumps from classical ABC family (Mycobacterium tuberculosis, Mtb) were chosen as target antigens to identify CTL epitopes. HLA-A2 restricted candidate peptides from Rv2937, Rv2686c and Rv2687c of Mycobacterium tuberculosis were predicted, synthesized and tested. Five peptides could induce IFN-γ release and cytotoxic activity in PBMCs from HLA-A2(+) PPD(+) donors. Results from HLA-A2/K(b) transgenic mice immunization assay suggested that four peptides Rv2937-p168, Rv2937-p266, Rv2686c-p151, and Rv2686c-p181 could induce significant CTL response in vivo. These results suggested that these novel epitopes could be used as immunotherapy candidates to TB drug-resistance.

SUBMITTER: Zhai MX

PROVIDER: S-EPMC4582945 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response.

Zhai Ming-Xia MX Chen Fei F Zhao Yuan-Yuan YY Wu Ya-Hong YH Li Guo-Dong GD Gao Yan-Feng YF Qi Yuan-Ming YM

PeerJ 20150922

Overcoming drug-resistance is one of the major challenges to control tuberculosis (TB). The up-regulation of efflux pumps is one common mechanism that leads to drug-resistance. Therefore, immunotherapy targeting these efflux pump antigens could be promising strategy to be combined with current chemotherapy. Considering that CD8+ cytotoxic T lymphocytes (CTLs) induced by antigenic peptides (epitopes) could elicit HLA-restricted anti-TB immune response, efflux pumps from classical ABC family (Myco ...[more]

PMID: 26417538

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Project description:Latent tuberculosis infection (LTBI) is the primary source of tuberculosis (TB) but there is no suitable detection method to distinguish LTBI from active tuberculosis (ATB). In this study, five antigens of Mycobacterium tuberculosis belonging to LTBI and regions of difference (RDs) were selected to predict Th1 and cytotoxic T lymphocyte (CTL) epitopes. The immunodominant Th1 and CTL peptides were identified in mouse models, and their performance in distinguishing LTBI from ATB was determined in mice and humans. Ten Th1 and ten CTL immunodominant peptides were predicted and synthesized in vitro. The enzyme-linked immunosorbent spot assay results showed that the combination of five Th1 peptides (area under the curve [AUC] = 1, P < 0.0001; sensitivity = 100% and specificity = 93.33%), the combination of seven CTL peptides (AUC = 1, P < 0.0001; 100 and 95.24%), and the combination of four peptide pools (AUC = 1, P < 0.0001; sensitivity = 100% and specificity = 91.67%) could significantly discriminate mice with LTBI from mice with ATB or uninfected controls (UCs). The combined peptides or peptide pools induced significantly different cytokine levels between the three groups, improving their ability to differentiate ATB from LTBI. Furthermore, it was found that pool 2 could distinguish patients with ATB from UCs (AUC = 0.6728, P = 0.0041; sensitivity = 72.58% and specificity = 59.46%). The combination of Th1 and CTL immunodominant peptides derived from LTBI-RD antigens might be a promising strategy for diagnosing ATB and LTBI in mice and patients with ATB and uninfected controls. IMPORTANCE Latent tuberculosis infection (LTBI) is a challenging problem in preventing, diagnosing, and treating tuberculosis (TB). The innate and adaptive immune responses are essential for eliminating or killing the mycobacteria. Antigen-presenting cells (APCs) present and display mycobacterium peptides on their surfaces, and recognition between T cells and APCs is based on some essential peptides rather than the full-length protein. Therefore, the selection of candidate antigens and the prediction and screening of potential immunodominant peptides have become a key to designing a new generation of TB diagnostic biomarkers. This study is the first to report that the combination of Th1 and CTL immunodominant peptides derived from LTBI-RD antigens can distinguish LTBI from active TB (ATB) in animals and ATB patients from uninfected individuals. These findings provide a novel insight for discovering potential biomarkers for the differential diagnosis of ATB and LTBI in the future.

Project description:BackgroundIt was previously shown that GlnA3sc enabled Streptomyces coelicolor to survive in excess polyamines. However, subsequent studies revealed that Rv1878, the corresponding Mycobacterium tuberculosis (M.tb) ortholog, was not essential for the detoxification of spermine (Spm), in M.tb. On the other hand, the multi-drug efflux pump Rv1877 was previously shown to enable export of a wide range of compounds, while Rv0191 was shown to be more specific to chloramphenicol.RationaleTherefore, we first wanted to determine if detoxification of Spm by efflux can be achieved by any efflux pump, or if that was dependent upon the function of the pump. Next, since Rv1878 was found not to be essential for the detoxification of Spm, we sought to follow-up on the investigation of the physiological role of Rv1878 along with Rv1877 and Rv0191.ApproachTo evaluate the specificity of efflux pumps in the mycobacterial tolerance to Spm, we generated unmarked ∆rv1877 and ∆rv0191 M.tb mutants and evaluated their susceptibility to Spm. To follow up on the investigation of any other physiological roles they may have, we characterized them along with the ∆rv1878 M.tb mutant.ResultsThe ∆rv1877 mutant was sensitive to Spm stress, while the ∆rv0191 mutant was not. On the other hand, the ∆rv1878 mutant grew better than the wild-type during iron starvation yet was sensitive to cell wall stress. The proteins Rv1877 and Rv1878 seemed to play physiological roles during hypoxia and acidic stress. Lastly, the ∆rv0191 mutant was the only mutant that was sensitive to oxidative stress.ConclusionThe multidrug MFS-type efflux pump Rv1877 is required for Spm detoxification, as opposed to Rv0191 which seems to play a more specific role. Moreover, Rv1878 seems to play a role in the regulation of iron homeostasis and the reconstitution of the cell wall of M.tb. On the other hand, the sensitivity of the ∆rv0191 mutant to oxidative stress, suggests that Rv0191 may be responsible for the transport of low molecular weight thiols.

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Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response.

Publications

Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response.

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