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Journal of Bacteriology, June 2007, p. 4234-4242, Vol. 189, No. 11
0021-9193/07/$08.00+0     doi:10.1128/JB.00201-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mycobacterium tuberculosis SigF Regulates Genes Encoding Cell Wall-Associated Proteins and Directly Regulates the Transcriptional Regulatory Gene phoY1 ^,

Ernest P. Williams,¹ Jong-Hee Lee,¹ William R. Bishai,^1,3 Carlo Colantuoni,² and Petros C. Karakousis^1*

Department of Medicine, Johns Hopkins University School of Medicine,¹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health,² Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland³

Received 6 February 2007/ Accepted 15 March 2007

Mycobacterium tuberculosis SigF is homologous to stress response and sporulation sigma factors in many bacteria. Consistent with a possible role in mycobacterial survival under stress conditions, M. tuberculosis sigF is strongly induced within cultured human macrophages and upon nutrient starvation, and SigF has been implicated in M. tuberculosis entry into stationary phase. On the other hand, SigF appears to contribute to the immune pathology of tuberculosis (TB), and a sigF-deficient mutant has altered cell membrane properties. Using an M. tuberculosis sigF deletion mutant, we show here that sigF is not required for bacillary survival under nutrient starvation conditions and within activated murine macrophages or for extracellular persistence in an in vivo granuloma model of latent TB infection. Using a chemically inducible recombinant strain to conditionally overexpress sigF, we did not observe arrest or retardation of growth in exponentially growing cultures or reduced susceptibility to rifampin and isoniazid. Consistent with our hypothesis that SigF may mediate TB immunopathogenesis by altering cell membrane properties, we found that overexpression of sigF resulted in the differential regulation of many cell wall-associated proteins, including members of the MmpL, PE, and PPE families, several of which have been shown to influence host-pathogen interactions. The most highly upregulated gene by quantitative reverse transcription-PCR at all time points following sigF induction was Rv3301c (phoY1), which encodes a probable transcriptional regulatory protein homologous to PhoU proteins involved in regulation of phosphate uptake. Using in vitro transcription analysis, we show that SigF directly regulates phoY1, whose proposed promoter sequence is GGATTG-N₁₆-GGGTAT.

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* Corresponding author. Mailing address: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, Room 106, Baltimore, MD 21231-1001. Phone: (410) 502-8233. Fax: (410) 614-8173. E-mail: petros{at}jhmi.edu

Published ahead of print on 23 March 2007.

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

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Journal of Bacteriology, June 2007, p. 4234-4242, Vol. 189, No. 11
0021-9193/07/$08.00+0     doi:10.1128/JB.00201-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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