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Journal of Bacteriology, October 2004, p. 6605-6616, Vol. 186, No. 19
0021-9193/04/$08.00+0     DOI: 10.1128/JB.186.19.6605-6616.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Transcription Regulation by the Mycobacterium tuberculosis Alternative Sigma Factor SigD and Its Role in Virulence{dagger}

Sahadevan Raman,1 Rohan Hazra,1,{ddagger} Christopher C. Dascher,2 and Robert N. Husson1*

Division of Infectious Diseases, Children's Hospital of Boston,1 Rheumatology and Immunology Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts2

Received 12 April 2004/ Accepted 2 July 2004

Mycobacterium tuberculosis, an obligate mammalian pathogen, adapts to its host during the course of infection via the regulation of gene expression. Of the regulators of transcription that play a role in this response, several alternative sigma factors of M. tuberculosis have been shown to control gene expression in response to stresses, and some of these are required for virulence or persistence in vivo. For this study, we examined the role of the alternative sigma factor SigD in M. tuberculosis gene expression and virulence. Using microarray analysis, we identified several genes whose expression was altered in a strain with a sigD deletion. A small number of these genes, including sigD itself, the gene encoding the autocrine growth factor RpfC, and a gene of unknown function, Rv1815, appear to be directly regulated by this sigma factor. By identifying the in vivo promoters of these genes, we have determined a consensus promoter sequence that is putatively recognized by SigD. The expression of several genes encoding PE-PGRS proteins, part of a large family of related genes of unknown function, was significantly increased in the sigD mutant. We found that the expression of sigD is stable throughout log phase and stationary phase but that it declines rapidly with oxygen depletion. In a mouse infection model, the sigD mutant strain was attenuated, with differences in survival and the inflammatory response in the lung between mice infected with the mutant and those infected with the wild type.

* Corresponding author. Mailing address: Children's Hospital, Division of Infectious Diseases, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 355-5151. Fax: (617) 730-0254. E-mail: robert.husson{at}childrens.harvard.edu.

{dagger} Supplemental material for this article may be found at http://jb.asm.org.

{ddagger} Present address: HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892.

Journal of Bacteriology, October 2004, p. 6605-6616, Vol. 186, No. 19
0021-9193/04/$08.00+0     DOI: 10.1128/JB.186.19.6605-6616.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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