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Impact of immunopathology on the antituberculous activity of pyrazinamide
In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA’s unique contribution to efficacy have remained controversial, and animal efficacy da...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080910/ https://www.ncbi.nlm.nih.gov/pubmed/30018074 http://dx.doi.org/10.1084/jem.20180518 |
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author | Blanc, Landry Sarathy, Jansy Passiflora Alvarez Cabrera, Nadine O’Brien, Paul Dias-Freedman, Isabela Mina, Marizel Sacchettini, James Savic, Radojka M. Gengenbacher, Martin Podell, Brendan K. Prideaux, Brendan Ioerger, Thomas Dick, Thomas Dartois, Véronique |
author_facet | Blanc, Landry Sarathy, Jansy Passiflora Alvarez Cabrera, Nadine O’Brien, Paul Dias-Freedman, Isabela Mina, Marizel Sacchettini, James Savic, Radojka M. Gengenbacher, Martin Podell, Brendan K. Prideaux, Brendan Ioerger, Thomas Dick, Thomas Dartois, Véronique |
author_sort | Blanc, Landry |
collection | PubMed |
description | In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA’s unique contribution to efficacy have remained controversial, and animal efficacy data vary across species. To understand how PZA kills bacterial populations present in critical lung lesion compartments, we first characterized a rabbit model of active TB, showing striking similarities in lesion types and fates to nonhuman primate models deemed the most appropriate surrogates of human TB. We next employed this model with lesion-centric molecular and bacteriology readouts to demonstrate that PZA exhibits potent activity against Mycobacterium tuberculosis residing in difficult-to-sterilize necrotic lesions. Our data also indicate that PZA is slow acting, suggesting that PZA administration beyond the first 2 mo may accelerate the cure. In conclusion, we provide a pharmacodynamic explanation for PZA’s treatment-shortening effect and deliver new tools to dissect the contribution of immune response versus drug at the lesion level. |
format | Online Article Text |
id | pubmed-6080910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-60809102018-08-08 Impact of immunopathology on the antituberculous activity of pyrazinamide Blanc, Landry Sarathy, Jansy Passiflora Alvarez Cabrera, Nadine O’Brien, Paul Dias-Freedman, Isabela Mina, Marizel Sacchettini, James Savic, Radojka M. Gengenbacher, Martin Podell, Brendan K. Prideaux, Brendan Ioerger, Thomas Dick, Thomas Dartois, Véronique J Exp Med Research Articles In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA’s unique contribution to efficacy have remained controversial, and animal efficacy data vary across species. To understand how PZA kills bacterial populations present in critical lung lesion compartments, we first characterized a rabbit model of active TB, showing striking similarities in lesion types and fates to nonhuman primate models deemed the most appropriate surrogates of human TB. We next employed this model with lesion-centric molecular and bacteriology readouts to demonstrate that PZA exhibits potent activity against Mycobacterium tuberculosis residing in difficult-to-sterilize necrotic lesions. Our data also indicate that PZA is slow acting, suggesting that PZA administration beyond the first 2 mo may accelerate the cure. In conclusion, we provide a pharmacodynamic explanation for PZA’s treatment-shortening effect and deliver new tools to dissect the contribution of immune response versus drug at the lesion level. Rockefeller University Press 2018-08-06 /pmc/articles/PMC6080910/ /pubmed/30018074 http://dx.doi.org/10.1084/jem.20180518 Text en © 2018 Blanc et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Blanc, Landry Sarathy, Jansy Passiflora Alvarez Cabrera, Nadine O’Brien, Paul Dias-Freedman, Isabela Mina, Marizel Sacchettini, James Savic, Radojka M. Gengenbacher, Martin Podell, Brendan K. Prideaux, Brendan Ioerger, Thomas Dick, Thomas Dartois, Véronique Impact of immunopathology on the antituberculous activity of pyrazinamide |
title | Impact of immunopathology on the antituberculous activity of pyrazinamide |
title_full | Impact of immunopathology on the antituberculous activity of pyrazinamide |
title_fullStr | Impact of immunopathology on the antituberculous activity of pyrazinamide |
title_full_unstemmed | Impact of immunopathology on the antituberculous activity of pyrazinamide |
title_short | Impact of immunopathology on the antituberculous activity of pyrazinamide |
title_sort | impact of immunopathology on the antituberculous activity of pyrazinamide |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080910/ https://www.ncbi.nlm.nih.gov/pubmed/30018074 http://dx.doi.org/10.1084/jem.20180518 |
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