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Infection and Immunity, December 2006, p. 6895-6906, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01006-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Potential Source of Francisella tularensis Live Vaccine Strain Attenuation Determined by Genome Comparison{triangledown} ,{dagger}

Laurence Rohmer,1 Mitchell Brittnacher,1 Kerstin Svensson,5,6 Danielle Buckley,4 Eric Haugen,4 Yang Zhou,4 Jean Chang,4 Ruth Levy,4 Hillary Hayden,4 Mats Forsman,5 Maynard Olson,1,3,4 Anders Johansson,5,6 Rajinder Kaul,3,4 and Samuel I. Miller1,2,3*

Departments of Genome Sciences,1 Microbiology,2 Medicine,3 University of Washington Genome Center, University of Washington, Seattle, Washington 98195,4 NBC-Analysis, Division of NBC-Defence, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden,5 Department of Clinical Microbiology, Infectious Diseases, Umeå University, SE-901 85 Umeå, Sweden6

Received 26 June 2006/ Returned for modification 15 August 2006/ Accepted 15 September 2006

Francisella tularensis is a bacterial pathogen that causes the zoonotic disease tularemia and is important to biodefense. Currently, the only vaccine known to confer protection against tularemia is a specific live vaccine strain (designated LVS) derived from a virulent isolate of Francisella tularensis subsp. holarctica. The origin and source of attenuation of this strain are not known. To assist with the design of a defined live vaccine strain, we sought to determine the genetic basis of the attenuation of LVS. This analysis relied primarily on the comparison between the genome of LVS and Francisella tularensis holarctica strain FSC200, which differ by only 0.08% of their nucleotide sequences. Under the assumption that the attenuation was due to a loss of function(s), only coding regions were examined in this comparison. To complement this analysis, the coding regions of two slightly more distantly related Francisella tularensis strains were also compared against the LVS coding regions. Thirty-five genes show unique sequence variations predicted to alter the protein sequence in LVS compared to the other Francisella tularensis strains. Due to these polymorphisms, the functions of 15 of these genes are very likely lost or impaired. Seven of these genes were demonstrated to be under stronger selective constraints, suggesting that they are the most probable to be the source of LVS attenuation and useful for a newly defined vaccine.

* Corresponding author. Mailing address: Department of Medicine, University of Washington, 1959 NE Pacific St., Campus Box 357710, Seattle, WA 98195. Phone: (206) 616-5110. Fax: (206) 616-5109. E-mail: millersi{at}u.washington.edu.

{triangledown} Published ahead of print on 25 September 2006.

Editor: V. J. DiRita

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

Infection and Immunity, December 2006, p. 6895-6906, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01006-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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