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Infection and Immunity, June 2008, p. 2333-2340, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01515-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates{triangledown}

Laura E. Via,1 P. Ling Lin,2,3 Sonja M. Ray,1 Jose Carrillo,1 Shannon Sedberry Allen,4 Seok Yong Eum,5 Kimberly Taylor,6 Edwin Klein,7 Ujjini Manjunatha,1 Jacqueline Gonzales,1 Eun Gae Lee,1 Seung Kyu Park,5,8 James A. Raleigh,9 Sang Nae Cho,10 David N. McMurray,4 JoAnne L. Flynn,3 and Clifton E. Barry III1*

Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda,1 Comparative Medicine Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, Maryland,6 Department of Pediatrics, Children's Hospital of Pittsburgh,2 Department of Molecular Genetics and Biochemistry,3 Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,7 College of Medicine, Texas A&M University System Health Science Center, College Station, Texas,4 International Tuberculosis Research Center,5 National Masan Tuberculosis Hospital, Ministry of Health and Welfare, Masan,8 Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea,10 Department of Radiobiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina9

Received 14 November 2007/ Returned for modification 27 December 2007/ Accepted 7 March 2008

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.

* Corresponding author. Mailing address: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20852. Phone: (301) 435-7509. Fax: (301) 480-5712. E-mail: cbarry{at}mail.nih.gov

{triangledown} Published ahead of print on 17 March 2008.

Editor: F. C. Fang

Infection and Immunity, June 2008, p. 2333-2340, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01515-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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