NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans
Abstract During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 −/− mice incapable of...
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doaj-653956e7764245f0bc27af8e6d730cfa2020-12-08T01:25:21ZengNature Publishing GroupScientific Reports2045-23222017-08-017111010.1038/s41598-017-09177-2NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humansMartin Gengenbacher0Maria A. Duque-Correa1Peggy Kaiser2Stefanie Schuerer3Doris Lazar4Ulrike Zedler5Stephen T. Reece6Amit Nayyar7Stewart T. Cole8Vadim Makarov9Clifton E. Barry III10Véronique Dartois11Stefan H. E. Kaufmann12Max Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyMax Planck Institute for Infection Biology, Department of ImmunologyTuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Health-National Institute of Allergy and Infectious DiseasesGlobal Health Institute, École Polytechnique Fédérale de LausanneA. N. Bakh Institute of Biochemistry, Russian Academy of ScienceTuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Health-National Institute of Allergy and Infectious DiseasesPublic Health Research Institute, Rutgers, The State University of New JerseyMax Planck Institute for Infection Biology, Department of ImmunologyAbstract During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 −/− mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 −/− mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 −/− mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 −/− mice are a predictive TB drug development tool owing to their consistent development of human-like pathology.https://doi.org/10.1038/s41598-017-09177-2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Martin Gengenbacher Maria A. Duque-Correa Peggy Kaiser Stefanie Schuerer Doris Lazar Ulrike Zedler Stephen T. Reece Amit Nayyar Stewart T. Cole Vadim Makarov Clifton E. Barry III Véronique Dartois Stefan H. E. Kaufmann |
spellingShingle |
Martin Gengenbacher Maria A. Duque-Correa Peggy Kaiser Stefanie Schuerer Doris Lazar Ulrike Zedler Stephen T. Reece Amit Nayyar Stewart T. Cole Vadim Makarov Clifton E. Barry III Véronique Dartois Stefan H. E. Kaufmann NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans Scientific Reports |
author_facet |
Martin Gengenbacher Maria A. Duque-Correa Peggy Kaiser Stefanie Schuerer Doris Lazar Ulrike Zedler Stephen T. Reece Amit Nayyar Stewart T. Cole Vadim Makarov Clifton E. Barry III Véronique Dartois Stefan H. E. Kaufmann |
author_sort |
Martin Gengenbacher |
title |
NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
title_short |
NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
title_full |
NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
title_fullStr |
NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
title_full_unstemmed |
NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
title_sort |
nos2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
Abstract During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 −/− mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 −/− mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 −/− mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 −/− mice are a predictive TB drug development tool owing to their consistent development of human-like pathology. |
url |
https://doi.org/10.1038/s41598-017-09177-2 |
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