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Infect. Immun. doi:10.1128/IAI.01006-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Potential source of Francisella tularensis live vaccine strain attenuation determined by genome comparison

Departments of Genome Sciences, Microbiology, Medicine, University of Washington Genome Center, University of Washington, Seattle, WA 98195; NBC-Analysis, Division of NBC-Defence, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden; Department of Clinical Microbiology, Infectious Diseases, Umeå University, SE-901 85 Umeå, Sweden

^* To whom correspondence should be addressed. Email: millersi{at}u.washington.edu.

	Abstract

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 live vaccine strain (named LVS) derived from a Francisella tularensis ssp. holarctica virulent isolate. 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 the Francisella tularensis holarctica strain FSC200, which differ by only 0.08% of their nucleotide sequence. 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 variation predicted to alter the protein sequence in LVS compared to the other Francisella tularensis strains. Due to these polymorphisms, the functions of fifteen of these genes are very likely lost or impaired. Seven of these genes were demonstrated to be under stronger selective constraints, suggesting they are the most probable to be the source of LVS attenuation and useful for a newly defined vaccine.

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