Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates

Laura E. Via, P. Ling Lin, Sonja M. Ray, Jose Carrillo, Shannon Sedberry Allen, Yong Eum Seok, Kimberly Taylor, Edwin Klein, Ujjini Manjunatha, Jacqueline Gonzales, Gae Lee Eun, Kyu Park Seung, James A. Raleigh, Nae Cho Sang, David N. McMurray, Jo Anne L. Flynn, Clifton E. Barry

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Abstract

Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O2. Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 ± 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.

Original languageEnglish
Pages (from-to)2333-2340
Number of pages8
JournalInfection and Immunity
Volume76
Issue number6
DOIs
Publication statusPublished - 2008 Jun

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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    Via, L. E., Lin, P. L., Ray, S. M., Carrillo, J., Allen, S. S., Seok, Y. E., Taylor, K., Klein, E., Manjunatha, U., Gonzales, J., Eun, G. L., Seung, K. P., Raleigh, J. A., Sang, N. C., McMurray, D. N., Flynn, J. A. L., & Barry, C. E. (2008). Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infection and Immunity, 76(6), 2333-2340. https://doi.org/10.1128/IAI.01515-07