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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/653956e7764245f0bc27af8e6d730cfa
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spelling	oai:doaj.org-article:653956e7764245f0bc27af8e6d730cfa2021-12-02T12:32:13ZNOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans10.1038/s41598-017-09177-22045-2322https://doaj.org/article/653956e7764245f0bc27af8e6d730cfa2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09177-2https://doaj.org/toc/2045-2322Abstract 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.Martin GengenbacherMaria A. Duque-CorreaPeggy KaiserStefanie SchuererDoris LazarUlrike ZedlerStephen T. ReeceAmit NayyarStewart T. ColeVadim MakarovClifton E. Barry IIIVéronique DartoisStefan H. E. KaufmannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2017
url	https://doaj.org/article/653956e7764245f0bc27af8e6d730cfa
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NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans

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