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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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