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Infection and Immunity, March 2003, p. 1134-1140, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1134-1140.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Deletion of Two-Component Regulatory Systems Increases the Virulence of Mycobacterium tuberculosis

Tanya Parish,{dagger} Debbie A. Smith, Sharon Kendall,{ddagger} Nicola Casali,§ Gregory J. Bancroft, and Neil G. Stoker*

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom

Received 9 July 2001/ Returned for modification 21 August 2001/ Accepted 2 December 2002

Two-component regulatory signal transduction systems are widely distributed among bacteria and enable the organisms to make coordinated changes in gene expression in response to a variety of environmental stimuli. The genome sequence of Mycobacterium tuberculosis contains 11 complete two-component systems, four isolated homologous regulators, and three isolated homologous sensors. We have constructed defined mutations in six of these genes and measured virulence in a SCID mouse model. Mice infected with four of the mutants (deletions of devR, tcrXY, trcS, and kdpDE) died more rapidly than those infected with wild-type bacteria. The other two mutants (narL and Rv3220c) showed no change compared to the wild-type H37Rv strain. The most hypervirulent mutant (devR{Delta}) also grew more rapidly in the acute stage of infection in immunocompetent mice and in gamma interferon-activated macrophages. These results define a novel class of genes in this pathogen whose presence slows down its multiplication in vivo or increases its susceptibility to host killing mechanisms. Thus, M. tuberculosis actively maintains a balance between its own survival and that of the host.

* Corresponding author. Present address: Department of Pathology and Infectious Diseases, Royal Veterinary College, Royal College St., London NW1 0TU, United Kingdom. Phone: 44 (0) 20 7468 5272. Fax: 44 (0) 20 7468 5306. E-mail: nstoker{at}rvc.ac.uk.

Editor: S. H. E. Kaufmann

{dagger} Present address: Department of Medical Microbiology, Barts and the London, Queen Mary's School of Medicine and Dentistry, London E1 2AD, United Kingdom.

{ddagger} Present address: Department of Pathology and Infectious Diseases, Royal Veterinary College, London NW1 0TU, United Kingdom.

§ Present address: School of Public Health, University of California at Berkeley, Berkeley, CA 94720.

Infection and Immunity, March 2003, p. 1134-1140, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1134-1140.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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