title: Potential source of Francisella tularensis live vaccine strain attenuation determined by genome comparison.
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 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.
authors.affiliation: Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Rohmer
authors.forename: Mitchell
authors.initials: M
authors.lastname: Brittnacher
authors.forename: Kerstin
authors.initials: K
authors.lastname: Svensson
authors.forename: Danielle
authors.initials: D
authors.lastname: Buckley
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jean
authors.initials: J
authors.lastname: Chang
authors.forename: Ruth
authors.initials: R
authors.lastname: Levy
authors.forename: Hillary
authors.initials: H
authors.lastname: Hayden
authors.forename: Mats
authors.initials: M
authors.lastname: Forsman
authors.forename: Maynard
authors.initials: M
authors.lastname: Olson
authors.forename: Anders
authors.initials: A
authors.lastname: Johansson
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D001428:Bacterial Vaccines / Q000235:genetics*; D001483:Base Sequence; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005604:Francisella tularensis / Q000235:genetics* / Q000276:immunology*; D005798:Genes, Bacterial; D016680:Genome, Bacterial / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D014406:Tularemia / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000235:genetics
chemical_list: D001428:Bacterial Vaccines; D014613:Vaccines, Attenuated