Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions

Jamie Harper, Ciaran Skerry, Stephanie L. Davis, Rokeya Tasneen, Mariah Weir, Igor Kramnik, William R. Bishai, Martin G. Pomper, Eric L. Nuermberger, Sanjay K. Jain

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)595-602
Number of pages8
JournalJournal of Infectious Diseases
Volume205
Issue number4
DOIs
StatePublished - Feb 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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