This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Geiman, D. E.
Right arrow Articles by Bishai, W. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Geiman, D. E.
Right arrow Articles by Bishai, W. R.

 Previous Article  |  Next Article 

Infection and Immunity, March 2004, p. 1733-1745, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1733-1745.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Attenuation of Late-Stage Disease in Mice Infected by the Mycobacterium tuberculosis Mutant Lacking the SigF Alternate Sigma Factor and Identification of SigF-Dependent Genes by Microarray Analysis

Deborah E. Geiman,1 Deepak Kaushal,1,{dagger} Chiew Ko,1 Sandeep Tyagi,1 Yukari C. Manabe,1 Benjamin G. Schroeder,2,{ddagger} Robert D. Fleischmann,2 Norman E. Morrison,1 Paul J. Converse,1 Ping Chen,1,§ and William R. Bishai1*

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,1 The Institute for Genomic Research, Rockville, Maryland2

Received 30 September 2003/ Returned for modification 16 November 2003/ Accepted 9 December 2003

The Mycobacterium tuberculosis alternate sigma factor, SigF, is expressed during stationary growth phase and under stress conditions in vitro. To better understand the function of SigF we studied the phenotype of the M. tuberculosis {Delta}sigF mutant in vivo during mouse infection, tested the mutant as a vaccine in rabbits, and evaluated the mutant's microarray expression profile in comparison with the wild type. In mice the growth rates of the {Delta}sigF mutant and wild-type strains were nearly identical during the first 8 weeks after infection. At 8 weeks, the {Delta}sigF mutant persisted in the lung, while the wild type continued growing through 20 weeks. Histopathological analysis showed that both wild-type and mutant strains had similar degrees of interstitial and granulomatous inflammation during the first 12 weeks of infection. However, from 12 to 20 weeks the mutant strain showed smaller and fewer lesions and less inflammation in the lungs and spleen. Intradermal vaccination of rabbits with the M. tuberculosis {Delta}sigF strain, followed by aerosol challenge, resulted in fewer tubercles than did intradermal M. bovis BCG vaccination. Complete genomic microarray analysis revealed that 187 genes were relatively underexpressed in the absence of SigF in early stationary phase, 277 in late stationary phase, and only 38 genes in exponential growth phase. Numerous regulatory genes and those involved in cell envelope synthesis were down-regulated in the absence of SigF; moreover, the {Delta}sigF mutant strain lacked neutral red staining, suggesting a reduction in the expression of envelope-associated sulfolipids. Examination of 5'-untranslated sequences among the downregulated genes revealed multiple instances of a putative SigF consensus recognition sequence: GGTTTCX18GGGTAT. These results indicate that in the mouse the M. tuberculosis {Delta}sigF mutant strain persists in the lung but at lower bacterial burdens than wild type and is attenuated by histopathologic assessment. Microarray analysis has identified SigF-dependent genes and a putative SigF consensus recognition site.

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

Editor: W. A. Petri, Jr.

{dagger} Present address: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105.

{ddagger} Present address: Applied Biosystems, Foster City, CA 94404.

§ Present address: Sequella, Inc., Rockville, Md.

Infection and Immunity, March 2004, p. 1733-1745, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1733-1745.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Greenstein, A. E., Hammel, M., Cavazos, A., Alber, T. (2009). Interdomain Communication in the Mycobacterium tuberculosis Environmental Phosphatase Rv1364c. J. Biol. Chem. 284: 29828-29835 [Abstract] [Full Text]  
  • Goldstone, R. M., Goonesekera, S. D., Bloom, B. R., Sampson, S. L. (2009). The Transcriptional Regulator Rv0485 Modulates the Expression of a pe and ppe Gene Pair and Is Required for Mycobacterium tuberculosis Virulence. Infect. Immun. 77: 4654-4667 [Abstract] [Full Text]  
  • Fontan, P. A., Voskuil, M. I., Gomez, M., Tan, D., Pardini, M., Manganelli, R., Fattorini, L., Schoolnik, G. K., Smith, I. (2009). The Mycobacterium tuberculosis Sigma Factor {sigma}B Is Required for Full Response to Cell Envelope Stress and Hypoxia In Vitro, but It Is Dispensable for In Vivo Growth. J. Bacteriol. 191: 5628-5633 [Abstract] [Full Text]  
  • Torrelles, J. B, DesJardin, L. E, MacNeil, J., Kaufman, T. M, Kutzbach, B., Knaup, R., McCarthy, T. R, Gurcha, S. S, Besra, G. S, Clegg, S., Schlesinger, L. S (2009). Inactivation of Mycobacterium tuberculosis mannosyltransferase pimB reduces the cell wall lipoarabinomannan and lipomannan content and increases the rate of bacterial-induced human macrophage cell death. Glycobiology 19: 743-755 [Abstract] [Full Text]  
  • Mehra, S., Kaushal, D. (2009). Functional Genomics Reveals Extended Roles of the Mycobacterium tuberculosis Stress Response Factor {sigma}H. J. Bacteriol. 191: 3965-3980 [Abstract] [Full Text]  
  • Provvedi, R., Boldrin, F., Falciani, F., Palu, G., Manganelli, R. (2009). Global transcriptional response to vancomycin in Mycobacterium tuberculosis. Microbiology 155: 1093-1102 [Abstract] [Full Text]  
  • Gebhard, S., Humpel, A., McLellan, A. D., Cook, G. M. (2008). The alternative sigma factor SigF of Mycobacterium smegmatis is required for survival of heat shock, acidic pH and oxidative stress. Microbiology 154: 2786-2795 [Abstract] [Full Text]  
  • Lee, J.-H., Karakousis, P. C., Bishai, W. R. (2008). Roles of SigB and SigF in the Mycobacterium tuberculosis Sigma Factor Network. J. Bacteriol. 190: 699-707 [Abstract] [Full Text]  
  • Talaat, A. M., Ward, S. K., Wu, C.-W., Rondon, E., Tavano, C., Bannantine, J. P., Lyons, R., Johnston, S. A. (2007). Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling. J. Bacteriol. 189: 4265-4274 [Abstract] [Full Text]  
  • Williams, E. P., Lee, J.-H., Bishai, W. R., Colantuoni, C., Karakousis, P. C. (2007). Mycobacterium tuberculosis SigF Regulates Genes Encoding Cell Wall-Associated Proteins and Directly Regulates the Transcriptional Regulatory Gene phoY1. J. Bacteriol. 189: 4234-4242 [Abstract] [Full Text]  
  • Pang, X., Vu, P., Byrd, T. F., Ghanny, S., Soteropoulos, P., Mukamolova, G. V., Wu, S., Samten, B., Howard, S. T. (2007). Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis. Microbiology 153: 1229-1242 [Abstract] [Full Text]  
  • Rodrigue, S., Brodeur, J., Jacques, P.-E., Gervais, A. L., Brzezinski, R., Gaudreau, L. (2007). Identification of Mycobacterial {sigma} Factor Binding Sites by Chromatin Immunoprecipitation Assays. J. Bacteriol. 189: 1505-1513 [Abstract] [Full Text]  
  • Agarwal, N., Tyagi, A. K. (2006). Mycobacterial transcriptional signals: requirements for recognition by RNA polymerase and optimal transcriptional activity. Nucleic Acids Res 34: 4245-4257 [Abstract] [Full Text]  
  • Karls, R. K., Guarner, J., McMurray, D. N., Birkness, K. A., Quinn, F. D. (2006). Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis. Microbiology 152: 1591-1600 [Abstract] [Full Text]  
  • Dainese, E., Rodrigue, S., Delogu, G., Provvedi, R., Laflamme, L., Brzezinski, R., Fadda, G., Smith, I., Gaudreau, L., Palu, G., Manganelli, R. (2006). Posttranslational Regulation of Mycobacterium tuberculosis Extracytoplasmic-Function Sigma Factor {sigma}L and Roles in Virulence and in Global Regulation of Gene Expression. Infect. Immun. 74: 2457-2461 [Abstract] [Full Text]  
  • Kazmierczak, M. J., Wiedmann, M., Boor, K. J. (2005). Alternative Sigma Factors and Their Roles in Bacterial Virulence. Microbiol. Mol. Biol. Rev. 69: 527-543 [Abstract] [Full Text]  
  • Raman, S., Hazra, R., Dascher, C. C., Husson, R. N. (2004). Transcription Regulation by the Mycobacterium tuberculosis Alternative Sigma Factor SigD and Its Role in Virulence. J. Bacteriol. 186: 6605-6616 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»