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2.
J Intern Med ; 283(3): 303-313, 2018 03.
Article in English | MEDLINE | ID: mdl-29205566

ABSTRACT

BACKGROUND: Mycobacterium tuberculosis (MTB), the aetiological agent of tuberculosis (TB), is capable of interfering with the phagosome maturation pathway, by inhibiting phagosome-lysosome fusion and the autophagic process to ensure survival and replication in macrophages. Thus, it has been proposed that the modulation of autophagy may represent a therapeutic approach to reduce MTB viability by enhancing its clearance. OBJECTIVE: The aim of this study was to investigate whether transglutaminase type 2 (TG2) is involved in the pathogenesis of MTB. RESULTS: We have shown that either genetic or pharmacological inhibition of TG2 leads to a marked reduction in MTB replicative capacity. Infection of TG2 knockout mice demonstrated that TG2 is required for MTB intracellular survival in macrophages and host tissues. The same inhibitory effect can be reproduced in vitro using Z-DON, a specific inhibitor of the transamidating activity of TG2. Massive cell death observed in macrophages that properly express TG2 is hampered by the absence of the enzyme and can be largely reduced by the treatment of wild-type macrophages with the TG2 inhibitor. Our data suggest that reduced MTB replication in cells lacking TG2 is due to the impairment of LC3/autophagy homeostasis. Finally, we have shown that treatment of MTB-infected murine and human primary macrophages with cystamine, a TG2 inhibitor already tested in clinical studies, causes a reduction in intracellular colony-forming units in human macrophages similar to that achieved by the anti-TB drug capreomycin. CONCLUSION: These results suggest that inhibition of TG2 activity is a potential novel approach for the treatment of TB.


Subject(s)
GTP-Binding Proteins/metabolism , Mycobacterium tuberculosis/pathogenicity , Transglutaminases/metabolism , Tuberculosis/metabolism , Animals , Autophagy , Blotting, Western , Cells, Cultured , Disease Models, Animal , Macrophages/metabolism , Macrophages/ultrastructure , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Microscopy, Electron, Transmission , Protein Glutamine gamma Glutamyltransferase 2 , Tuberculosis/microbiology , Tuberculosis/pathology
3.
Tuberculosis (Edinb) ; 106: 38-43, 2017 09.
Article in English | MEDLINE | ID: mdl-28802403

ABSTRACT

The QuantiFERON-TB Gold Plus (QFT-Plus) represents the new QuantiFERON-TB Gold In-tube (QFT-GIT) to identify latent tuberculosis infection (LTBI). The main differences is the addition of a new tube containing shorter peptides stimulating CD8 T-cells. Aim of this study is to evaluate the accuracy of QFT-Plus compared with QFT-GIT in a cross sectional study of individuals with or without tuberculosis (TB). We enrolled 179 participants: 19 healthy donors, 58 LTBI, 33 cured TB and 69 active TB. QFT-Plus and QFT-GIT were performed. The two tests showed a substantial agreement. Moreover we found a similar sensitivity in active TB and same specificity in healthy donors. A higher proportion of the LTBI subjects responded to both TB1 and TB2 compared to those with active TB (97% vs 81%). Moreover, a selective response to TB2 was associated with active TB (9%) and with a severe TB disease, suggesting that TB2 stimulation induces a CD8 T-cell response in absence of a CD4-response. In conclusion, QFT-Plus and QFT-GIT assays showed a substantial agreement and similar accuracy for active TB detection. Interestingly, a higher proportion of the LTBI subjects responded concomitantly to TB1 and TB2 compared to those with active TB, whereas a selective TB2 response associated with active TB.


Subject(s)
CD8-Positive T-Lymphocytes/microbiology , Interferon-gamma Release Tests/methods , Interferon-gamma/metabolism , Latent Tuberculosis/diagnosis , Lymphocyte Activation , Mycobacterium tuberculosis/immunology , Adult , Antigens, Bacterial/immunology , Bacterial Load , Bacterial Proteins/immunology , Biomarkers/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Case-Control Studies , Cross-Sectional Studies , Female , Host-Pathogen Interactions , Humans , Interferon-gamma/immunology , Latent Tuberculosis/immunology , Latent Tuberculosis/microbiology , Male , Middle Aged , Mycobacterium tuberculosis/pathogenicity , Peptide Fragments/immunology , Predictive Value of Tests , Reproducibility of Results , Severity of Illness Index
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