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Infection and Immunity, February 2009, p. 598-603, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.01132-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Extrapulmonary Dissemination of Mycobacterium bovis but Not Mycobacterium tuberculosis in a Bronchoscopic Rabbit Model of Cavitary Tuberculosis{triangledown}

Gueno G. Nedeltchev,1 Tirumalai R. Raghunand,1,3 Mandeep S. Jassal,1,2 Shichun Lun,1 Qi-Jian Cheng,1,4 and William R. Bishai1*

Center for Tuberculosis Research,1 Division of Pediatric Pulmonology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231,2 Centre for Cellular and Molecular Biology, Hyderabad, India,3 Department of Pulmonary Medicine, Ruijin Hospital, Shanghai, China4

Received 10 September 2008/ Returned for modification 9 October 2008/ Accepted 20 November 2008

The rabbit model of tuberculosis is attractive because of its pathophysiologic resemblance to the disease in humans. Rabbits are naturally resistant to infection but may manifest cavitary lung lesions. We describe here a novel approach that utilizes presensitization and bronchoscopic inoculation to reliably produce cavities in the rabbit model. With a fixed inoculum of bacilli, we were able to reproducibly generate cavities by using Mycobacterium bovis Ravenel, M. bovis AF2122, M. bovis BCG, M. tuberculosis H37Rv, M. tuberculosis CDC1551, and the M. tuberculosis CDC1551 {Delta}sigC mutant. M. bovis infections generated cavitary CFU counts of 106 to 109 bacilli, while non-M. bovis species and BCG yielded CFU counts that ranged from 104 to 108 bacilli. Extrapulmonary dissemination was almost exclusively noted among rabbits infected with M. bovis Ravenel and AF2122. Though all of the species yielded secondary lesions at intrapulmonary sites, M. bovis infections led to the most apparent gross pathology. Using the M. tuberculosis icl and dosR gene expression patterns as molecular sentinels, we demonstrated that both the cavity wall and cavity lumen are microenvironments associated with hypoxia, upregulation of the bacterial dormancy program, and the use of host lipids for bacterial catabolism. This unique cavitary model provides a reliable animal model to study cavity pathogenesis and extrapulmonary dissemination.

* Corresponding author. Mailing address: Center for Tuberculosis Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, 1550 Orleans Street, Room 108, Baltimore, MD 21231-1001. Phone: (410) 955-3507. Fax: (410) 614-8173. E-mail: wbishai{at}jhmi.edu

{triangledown} Published ahead of print on 8 December 2008.

Editor: W. A. Petri, Jr.

Infection and Immunity, February 2009, p. 598-603, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.01132-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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