title: Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions.
abstract: BACKGROUND
  Preclinical evaluation of tuberculosis drugs is generally limited to mice. However, necrosis and hypoxia, key features of human tuberculosis lesions, are lacking in conventional mouse strains.
  
  
  METHODS
  We used C3HeB/FeJ mice, which develop necrotic lesions in response to Mycobacterium tuberculosis infection. Positron emission tomography in live infected animals, postmortem pimonidazole immunohistochemistry, and bacterial gene expression analyses were used to assess whether tuberculosis lesions in C3HeB/FeJ are hypoxic. Efficacy of combination drug treatment, including PA-824, active against M. tuberculosis under hypoxic conditions, was also evaluated.
  
  
  RESULTS
  Tuberculosis lesions in C3HeB/FeJ (but not BALB/c) were found to be hypoxic and associated with up-regulation of known hypoxia-associated bacterial genes (P < .001). Contrary to sustained activity reported elsewhere in BALB/c mice, moxifloxacin and pyrazinamide (MZ) combination was not bactericidal beyond 3 weeks in C3HeB/FeJ. Although PA-824 added significant activity, the novel combination of PA-824 and MZ was less effective than the standard first-line regimen in C3HeB/FeJ.
  
  
  CONCLUSIONS
  We demonstrate that tuberculosis lesions in C3HeB/FeJ are hypoxic. Activities of some key tuberculosis drug regimens in development are represented differently in C3HeB/FeJ versus BALB/c mice. Because C3HeB/FeJ display key features of human tuberculosis, this strain warrants evaluation as a more pathologically relevant model for preclinical studies.
authors.affiliation: Department of Medicine, Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Harper
authors.forename: Ciaran
authors.initials: C
authors.lastname: Skerry
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Davis
authors.forename: Rokeya
authors.initials: R
authors.lastname: Tasneen
authors.forename: Mariah
authors.initials: M
authors.lastname: Weir
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage; D001372:Aza Compounds / Q000008:administration & dosage; D004195:Disease Models, Animal; D024841:Fluoroquinolones; D020869:Gene Expression Profiling; D005798:Genes, Bacterial; D006099:Granuloma / Q000150:complications* / Q000473:pathology*; D000860:Hypoxia / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D009593:Nitroimidazoles / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D011718:Pyrazinamide / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009593:Nitroimidazoles; D011804:Quinolines; C410767:pretomanid; D011718:Pyrazinamide; D000077266:Moxifloxacin