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1 June 2007

Volume 195, Number 11
The Journal of Infectious Diseases 2007;195:1634–1642
© 2007 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2007/19511-0012$15.00
DOI: 10.1086/517526
MAJOR ARTICLE

Accelerated Detection of Mycobacterium tuberculosis Genes Essential for Bacterial Survival in Guinea Pigs, Compared with Mice

Sanjay K. Jain,1,2,a

S. Moises Hernandez‐Abanto,1,a

Qi‐Jian Cheng,1

Prabhpreet Singh,1

Lan H. Ly,3

Lee G. Klinkenberg,1

Norman E. Morrison,1

Paul J. Converse,1

Eric Nuermberger,1

Jacques Grosset,1

David N. McMurray,3

Petros C. Karakousis,1

Gyanu Lamichhane,1 and

William R. Bishai1

1Center for Tuberculosis Research and 2Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland; 3Department of Microbial and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station

Background.Mouse and guinea pig models have been used to identify Mycobacterium tuberculosis mutants attenuated for survival. However, unlike mice, M. tuberculosis–infected guinea pigs form caseating granulomas, which may simulate human disease more closely.

Methods.We used designer arrays for defined mutant analysis, a high‐throughput subtractive competition assay, for genotypically defined M. tuberculosis mutants and compared the survival of the same mutant pools in guinea pig and mouse aerosol models. Selected mutants found to be attenuated in either aerosol model were also analyzed in the mouse hollow‐fiber model.

Results.M. tuberculosis mutants representing 74 genes were tested. Eighteen M. tuberculosis mutants were attenuated for survival in either aerosol model, with 70% of selected mutants also attenuated in the mouse hollow‐fiber model. The majority of attenuated mutants in the mouse aerosol model were detected only after 90 days of infection. There was a high degree of concordance between the genes identified by the 2 aerosol models, with detection being significantly earlier in the guinea pig ( ).

Conclusions.We identified M. tuberculosis genes required for survival in mammalian lungs. The majority of mouse late‐stage survival mutants were detected significantly earlier in the guinea pig, which suggests that differences in tuberculosis‐induced lung pathologic changes may account for this accelerated detection.

Received 2 November 2006; accepted 21 December 2006; electronically published 23 April 2007.

Reprints or correspondence: Dr. Sanjay K. Jain, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans St., Baltimore, MD 21231 ().

Cited by

Nicholas A. Be, Gyanu Lamichhane, Jacques Grosset, Sandeep Tyagi, Qi-Jian Cheng, Kwang Sik Kim, William R. Bishai, and Sanjay K. Jain. (2008) Murine Model to Study the Invasion and Survival of Mycobacterium tuberculosis in the Central Nervous System. The Journal of Infectious Diseases 198:10, 1520-1528
Online publication date: 15-Nov-2008.
Abstract-Full Text-PDF Version (417 kB)

  • Potential conflicts of interest: none reported.

    Financial support: National Institutes of Health (grants and contracts AI36973, AI43846, AI37856, and N01 AI30036).

  • S.K.J. and S.M.H.‐A. contributed equally to the study.

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