Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-09177-2
Title: NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans
Authors: Gengenbacher, M 
Duque-Correa, M.A
Kaiser, P
Schuerer, S
Lazar, D
Zedler, U
Reece, S.T
Nayyar, A
Cole, S.T
Makarov, V
Barry, C.E
Dartois, V
Kaufmann, S.H.E
Keywords: inducible nitric oxide synthase
isoniazid
Nos2 protein, mouse
rifampicin
rifapentine
tuberculostatic agent
analogs and derivatives
animal
deficiency
disease model
fibrosis
foam cell
genetics
human
hypoxia
immunology
knockout mouse
lung tuberculosis
metabolism
mouse
necrosis
pathology
treatment outcome
Animals
Antitubercular Agents
Disease Models, Animal
Fibrosis
Foam Cells
Humans
Hypoxia
Isoniazid
Mice
Mice, Knockout
Necrosis
Nitric Oxide Synthase Type II
Rifampin
Treatment Outcome
Tuberculosis, Pulmonary
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Gengenbacher, M, Duque-Correa, M.A, Kaiser, P, Schuerer, S, Lazar, D, Zedler, U, Reece, S.T, Nayyar, A, Cole, S.T, Makarov, V, Barry, C.E, Dartois, V, Kaufmann, S.H.E (2017). NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans. Scientific Reports 7 (1) : 8853. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-09177-2
Rights: Attribution 4.0 International
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. © 2017 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/178592
ISSN: 2045-2322
DOI: 10.1038/s41598-017-09177-2
Rights: Attribution 4.0 International
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