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 Sebastian, S.
Right arrow Articles by Kasper, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sebastian, S.
Right arrow Articles by Kasper, D. L.

 Previous Article  |  Next Article 

Infection and Immunity, May 2007, p. 2591-2602, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01789-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Defined O-Antigen Polysaccharide Mutant of Francisella tularensis Live Vaccine Strain Has Attenuated Virulence while Retaining Its Protective Capacity{triangledown}

Shite Sebastian,1,2 Simon T. Dillon,3 Jillian G. Lynch,1 LeeAnn T. Blalock,1 Emmy Balon,3 Kristin T. Lee,1 Laurie E. Comstock,2 J. Wayne Conlan,4 Eric J. Rubin,3 Arthur O. Tzianabos,1,2 and Dennis L. Kasper1,2*

Department of Microbiology and Molecular Genetics,1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School,2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115,3 National Research Council Canada, Institute for Biological Sciences, Ottawa, Ontario KIA OR6, Canada4

Received 9 November 2006/ Returned for modification 3 December 2006/ Accepted 3 February 2007

Francisella tularensis, the causative agent of tularemia, has been designated a CDC category A select agent because of its low infective dose (<10 CFU), its ready transmission by aerosol, and its ability to produce severe morbidity and high mortality. The identification and characterization of this organism's virulence determinants will facilitate the development of a safe and effective vaccine. We report that inactivation of the wbtA-encoded dehydratase of the O-antigen polysaccharide (O-PS) locus of the still-unlicensed live vaccine strain of F. tularensis (LVS) results in a mutant (the LVS wbtA mutant) with remarkably attenuated virulence. Western blot analysis and immune electron microscopy studies associate this loss of virulence with a complete lack of surface O-PS expression. A likely mechanism for attenuation is shown to be the transformation from serum resistance in the wild-type strain to serum sensitivity in the mutant. Despite this significant attenuation in virulence, the LVS wbtA mutant remains immunogenic and confers protective immunity on mice against challenge with an otherwise lethal dose of either F. tularensis LVS or a fully virulent clinical isolate of F. tularensis type B. Recognition and characterization of the pivotal role of O-PS in the virulence of this intracellular bacterial pathogen may have broad implications for the creation of a safe and efficacious vaccine.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115. Phone: (617) 525-2280. Fax: (617) 525-0080. E-mail: dennis_kasper{at}hms.harvard.edu

{triangledown} Published ahead of print on 12 February 2007.

Editor: A. Casadevall

Infection and Immunity, May 2007, p. 2591-2602, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01789-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ray, H. J., Cong, Y., Murthy, A. K., Selby, D. M., Klose, K. E., Barker, J. R., Guentzel, M. N., Arulanandam, B. P. (2009). Oral Live Vaccine Strain-Induced Protective Immunity against Pulmonary Francisella tularensis Challenge Is Mediated by CD4+ T Cells and Antibodies, Including Immunoglobulin A. CVI 16: 444-452 [Abstract] [Full Text]  
  • Cole, L. E., Yang, Y., Elkins, K. L., Fernandez, E. T., Qureshi, N., Shlomchik, M. J., Herzenberg, L. A., Herzenberg, L. A., Vogel, S. N. (2009). Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge. Proc. Natl. Acad. Sci. USA 106: 4343-4348 [Abstract] [Full Text]  
  • Qin, A., Scott, D. W., Thompson, J. A., Mann, B. J. (2009). Identification of an Essential Francisella tularensis subsp. tularensis Virulence Factor. Infect. Immun. 77: 152-161 [Abstract] [Full Text]  
  • Clay, C. D., Soni, S., Gunn, J. S., Schlesinger, L. S. (2008). Evasion of Complement-Mediated Lysis and Complement C3 Deposition Are Regulated by Francisella tularensis Lipopolysaccharide O Antigen. J. Immunol. 181: 5568-5578 [Abstract] [Full Text]  
  • Goebel, E. M., Wolfe, D. N., Elder, K., Stibitz, S., Harvill, E. T. (2008). O Antigen Protects Bordetella parapertussis from Complement. Infect. Immun. 76: 1774-1780 [Abstract] [Full Text]  
  • Maier, T. M., Casey, M. S., Becker, R. H., Dorsey, C. W., Glass, E. M., Maltsev, N., Zahrt, T. C., Frank, D. W. (2007). Identification of Francisella tularensis Himar1-Based Transposon Mutants Defective for Replication in Macrophages. Infect. Immun. 75: 5376-5389 [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»