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Infection and Immunity, October 2000, p. 5575-5580, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Construction and Characterization of a Mycobacterium tuberculosis Mutant Lacking the Alternate Sigma Factor Gene, sigF

Ping Chen,1 Rafael E. Ruiz,1 Qing Li,2 Richard F. Silver,2 and William R. Bishai1,3,*

Center for Tuberculosis Research, Department of International Health, Johns Hopkins University School of Public Health,1 and Department of Medicine, Johns Hopkins University School of Medicine,3 Baltimore, Maryland, and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio2

Received 20 March 2000/Returned for modification 15 May 2000/Accepted 26 June 2000

The alternate RNA polymerase sigma factor gene, sigF, which is expressed in stationary phase and under stress conditions in vitro, has been deleted in the virulent CDC1551 strain of Mycobacterium tuberculosis. The growth rate of the Delta sigF mutant was identical to that of the isogenic wild-type strain in exponential phase, although in stationary phase the mutant achieved a higher density than the wild type. The mutant showed increased susceptibility to rifampin and rifapentine. Additionally, the Delta sigF mutant displayed diminished uptake of chenodeoxycholate, and this effect was reversed by complementation with a wild-type sigF gene. No differences in short-term intracellular growth between mutant and wild-type organisms within human monocytes were observed. Similarly, the organisms did not differ in their susceptibilities to lymphocyte-mediated inhibition of intracellular growth. However, mice infected with the Delta sigF mutant showed a median time to death of 246 days compared with 161 days for wild-type strain-infected animals (P < 0.001). These data indicate that M. tuberculosis sigF is a nonessential alternate sigma factor both in axenic culture and for survival in macrophages in vitro. While the Delta sigF mutant produces a lethal infection of mice, it is less virulent than its wild-type counterpart by time-to-death analysis.

* Corresponding author. Mailing address: Center for Tuberculosis Research, Johns Hopkins University School of Public Health, 615 North Wolfe St., Baltimore, MD 21205-2179. Phone: (410) 955-3507. Fax: (410) 614-8173. E-mail: wbishai{at}jhsph.edu.

Infection and Immunity, October 2000, p. 5575-5580, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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