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Infection and Immunity, April 2005, p. 2533-2540, Vol. 73, No. 4
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.4.2533-2540.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Designer Arrays for Defined Mutant Analysis To Detect Genes Essential for Survival of Mycobacterium tuberculosis in Mouse Lungs

Gyanu Lamichhane,1 Sandeep Tyagi,1 and William R. Bishai1*

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland1

Received 8 September 2004/ Returned for modification 4 November 2004/ Accepted 22 November 2004

The mechanisms by which Mycobacterium tuberculosis elicits disease are complex, involving a large repertoire of bacterial genes that are required for in vivo growth and survival. To identify such genes, we utilized a high-throughput microarray detection method to rapidly screen hundreds of unique, genotypically defined transposon mutants for in vivo survival with a high degree of specificity and sensitivity. Thirty-one M. tuberculosis genes were found to be required for in vivo survival in mouse lungs. These genes are involved in a broad range of activities, including metabolism, cell wall functions, and regulation. Our screen included 11 of the 12 known members of the mycobacterial membrane protein (mmpL) family genes, and mutation of 6 of these genes—mmpL4, mmpL5, mmpL7, mmpL8, mmpL10, and mmpL11—severely compromised the ability of the mutants to multiply in mouse lungs. Most of the 31 genes are conserved in other pathogenic mycobacteria, including M. leprae and M. bovis, suggesting that a core of basic in vivo survival mechanisms may be highly conserved despite the divergent human pathology caused by members of the mycobacterial genus. Of the 31 genes reported here, 17 have not been previously described to be involved in in vivo growth and survival of M. tuberculosis.

* Corresponding author. Mailing address: Center for Tuberculosis Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins School of Medicine, 1503 E. Jefferson St., Rm. 112, Baltimore, MD 21231-1001. Phone: (410) 955-3507. Fax: (410) 614-8173. E-mail: wbishai{at}jhsph.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, April 2005, p. 2533-2540, Vol. 73, No. 4
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.4.2533-2540.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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