TY - JOUR
T1 - Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions
AU - Harper, Jamie
AU - Skerry, Ciaran
AU - Davis, Stephanie L.
AU - Tasneen, Rokeya
AU - Weir, Mariah
AU - Kramnik, Igor
AU - Bishai, William R.
AU - Pomper, Martin G.
AU - Nuermberger, Eric L.
AU - Jain, Sanjay K.
N1 - Funding Information:
Financial support. This work was supported by the National Institute of Health’s Director’s New Innovator Award (grant OD006492) and Bill and Melinda Gates Foundation TB Drug Accelerator grants (grants 48793 and 42851).
Funding Information:
Potential conflicts of interest. E. L. N. receives grant funding from sanofi-aventis, Global Alliance for TB Drug Development, Otsuka Pharmaceuticals, and Pfizer. S. K. J. and E. L. N. received travel/accommodation costs from sanofi-aventis for a nonpromotional lecture at the Satellite Symposium, 40th Union World Conference on Lung Health (December 2009; Cancun, Mexico). All other authors report no potential conflicts.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - 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.
AB - 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.
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U2 - 10.1093/infdis/jir786
DO - 10.1093/infdis/jir786
M3 - Article
C2 - 22198962
AN - SCOPUS:84856301870
SN - 0022-1899
VL - 205
SP - 595
EP - 602
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 4
ER -