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NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans

Martin Gengenbacher1,2, Maria A Duque-Correa3,4, Peggy Kaiser3

  • 1Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany. mg1435@njms.rutgers.edu.

Scientific Reports
|August 20, 2017
PubMed

Insights

Nos2-deficient mice develop human-like tuberculosis lung pathology, offering a better preclinical model. This model accurately predicts how drugs like isoniazid and moxifloxacin perform against tuberculosis.

Area of Science:

  • Tuberculosis research
  • Infectious disease modeling
  • Pharmacology

Background:

  • Human tuberculosis (TB) involves complex lung pathology with necrosis and hypoxia.
  • Standard mouse models (BALB/c) fail to replicate this human pathology, limiting predictive accuracy for drug development.
  • Nitric oxide synthase 2 knockout (Nos2-/-) mice consistently develop hypoxic necrotizing lung lesions, mimicking human TB.

Purpose of the Study:

  • To evaluate the impact of human-like hypoxic necrosis on antimycobacterial drug efficacy.
  • To assess the utility of Nos2-/- mice as a predictive preclinical model for tuberculosis drug development.

Main Methods:

  • Nos2-/- mice infected with TB were treated with monotherapy before or after the development of human-like pathology.
  • The efficacy of isoniazid, rifapentine, rifampin, pretomanid, delamanid, BTZ043, and linezolid was assessed.
  • The activity of moxifloxacin was evaluated in the presence of hypoxic necrotizing lesions.

Main Results:

  • Isoniazid induced drug tolerance only in the presence of necrotic lesions.
  • Rifapentine showed greater potency than rifampin before pathology development.
  • Pretomanid, delamanid, and BTZ043 were bactericidal regardless of pathology; linezolid was bacteriostatic but improved lung condition; moxifloxacin activity was reduced by hypoxic lesions.

Conclusions:

  • Nos2-/- mice provide a valuable and predictive preclinical model for tuberculosis drug development due to their consistent development of human-like pathology.
  • The presence of hypoxic necrotizing lesions significantly influences the efficacy of certain antimycobacterial drugs, impacting treatment outcomes.

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